U.S. patent number 7,109,351 [Application Number 09/651,207] was granted by the patent office on 2006-09-19 for fused pyrrolecarboxamides; gaba brain receptor ligands.
This patent grant is currently assigned to Neurogen Corporation. Invention is credited to Pamela Albaugh, Alan Hutchison, Kenneth Shaw.
United States Patent |
7,109,351 |
Albaugh , et al. |
September 19, 2006 |
Fused pyrrolecarboxamides; GABA brain receptor ligands
Abstract
Substituted pyrrolecarboxamide compounds are disclosed. These
compounds are highly selective agonists, antagonists or inverse
agonists for GABA.sub.A brain receptors or prodrugs of agonists,
antagonists or inverse agonists for GABA.sub.A brain receptors and
are therefore useful in the diagnosis and treatment of anxiety,
depression, Alzheimer's dementia, sleep and seizure disorders,
overdose with benzodiazepine drugs and for enhancement of memory.
Pharmaceutical compositions, including packaged pharmaceutical
compositions, are further provided. Compounds of the invention are
also useful as probes for the localization of GABA.sub.A receptors
in tissue samples.
Inventors: |
Albaugh; Pamela (Clinton,
CT), Shaw; Kenneth (Weston, CT), Hutchison; Alan
(Madison, CT) |
Assignee: |
Neurogen Corporation (Branford,
CT)
|
Family
ID: |
26848974 |
Appl.
No.: |
09/651,207 |
Filed: |
August 30, 2000 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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09387311 |
Aug 31, 1999 |
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Current U.S.
Class: |
548/492 |
Current CPC
Class: |
A61P
25/00 (20180101); C07D 409/12 (20130101); A61P
25/28 (20180101); C07D 403/12 (20130101); C07D
471/04 (20130101); A61K 51/047 (20130101); A61P
25/24 (20180101); A61P 43/00 (20180101); C07D
401/14 (20130101); C07D 417/14 (20130101); A61P
25/20 (20180101); C07D 209/42 (20130101); C07D
209/52 (20130101); C07D 401/12 (20130101); A61P
25/22 (20180101); G01N 2333/70571 (20130101) |
Current International
Class: |
C07D
209/42 (20060101); A61K 31/40 (20060101) |
Field of
Search: |
;548/492,465
;514/414,419 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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3246932 |
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0 054 507 |
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Jun 1982 |
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EP |
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183 458 |
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Jun 1986 |
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EP |
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WO 93/17025 |
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Sep 1993 |
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WO |
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WO 94/17095 |
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Aug 1994 |
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WO |
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WO 95/11885 |
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May 1995 |
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WO |
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WO 97/26243 |
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Jul 1997 |
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WO |
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WO 97/34870 |
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Sep 1997 |
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WO |
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WO 98/02420 |
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Jan 1998 |
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WO |
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WO 99/25684 |
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May 1999 |
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WO |
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9925684 |
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May 1999 |
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WO |
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9734670 |
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Sep 1999 |
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WO |
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Other References
Biere et al., Liebigs Ann. Chem., pp. 1749-1764. (1986), "Teach
assorted benzodiazepine agonists and antagonists and related
anti-depressant and central nervous system active compounds." cited
by other .
Carlock et al., J. Org. Chem., vol. 42, No. 11, pp. 1883-1885.
(1977), "3-Diazo-4-oxo-3,4-dihydroquinoline. A Novel Synthon for
Indole 3-carboxamides." cited by other .
Carlock et al., J. Heterocyclic Chem., vol. 14, pp. 519-520.
(1977), "A Noteworthy Improvement of the
3-Diazo-4-oxo-3,4-dihydroquinoline Photosynthesis of
Indole-3-carboxamides." cited by other.
|
Primary Examiner: Lambkin; Deborah C.
Attorney, Agent or Firm: Boehnen; McDonnell Hulbert &
Berghoff LLP
Parent Case Text
This application is a continuation-in-part of U.S. Ser. No.
09/387,311, filed Aug. 31, 1999, now abandoned.
Claims
What is claimed is:
1. A compound of the formula: ##STR00181## wherein Y is
independently selected at each occurrence from hydrogen, hydroxy,
halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, cyano,
nitro, amino, and mono- or dialkyl (C.sub.1-C.sub.6) amino; T is
halogen, hydrogen, hydroxyl, amino, alkyl or alkoxy; W is chosen
from --O--, --NH--, --NR.sub.7--, --S(O).sub.0-2--, --C(.dbd.O)--,
--OC(.dbd.O)--, --C(.dbd.O)O--, --C(.dbd.O)NH--, --NHC(.dbd.O)--,
--NR.sub.7C(.dbd.O)--, --NHS(O).sub.0-2--,
--NR.sub.7S(O).sub.0-2--, --S(O).sub.0-2NH--,
--S(O).sub.0-2R.sub.7H--, and CR.sub.7R.sub.8 where R.sub.7 and
R.sub.8 are the same or different and represent hydrogen, alkyl, or
R.sub.7-R.sub.8 taken together represents a cyclic moiety having
3-7 carbon atoms; Z is hydroxy, cycloalkyl (alkoxy), amino, mono-
or di (alkyl.sub.1)amino, azacycloalkyl, --O(alkyl.sub.1),
--S(O).sub.0-2(alkyl.sub.1), --OC(.dbd.O) (alkyl.sub.1),
--OC(.dbd.O)H, --C(.dbd.O)O(alkyl.sub.1), --C(.dbd.O)OH,
--C(.dbd.O)NH(alkyl.sub.1), --C(.dbd.O)NH.sub.2, --NHC(.dbd.O)
(alkyl.sub.1), --NHC(.dbd.O)H, --N(alkyl.sub.1)C(.dbd.O)
(alkyl.sub.1), --NHS(O).sub.0-2(alkyl.sub.1),
--N(alkyl.sub.1)S(O).sub.0-2(alkyl.sub.1),
--S(O).sub.0-2NH(alkyl.sub.1), or
--S(O).sub.0-2(alkyl.sub.1)N(alkyl.sub.1), wherein alkyl.sub.1 is
independently chosen at each occurrence and is straight, branched,
or cyclic, may contain one or two double or triple bonds, and is
unsubstituted or substituted with one or more substitutents
selected from: hydroxy, oxo, halogen, amino, cyano, nitro, and
alkoxy, or Z is phenyl or phenylalkyl where the phenyl portion is
optionally substituted with alkyl, hydroxy, alkoxy,
trifluoromethyl, halogen, amino, or mono- or di-alkylamino, or Z is
NR.sub.9COR.sub.10 where R.sub.9 and R.sub.10 are the same or
different and represent hydrogen or alkyl or cycloalkyl, or Z is
connected, optionally through W, to Q to from a 1-6 membered ring;
or Z represents a group of the formula: ##STR00182## p is 1, 2, or
3; q is 0, 1, or 2; and R.sub.z is hydrogen or alkyl; or Z is a
group of the formula: ##STR00183## where s is 0, 1, 2 or 3, and the
sum of s and m is not less than 1; R.sub.o is hydroxy,
C.sub.1-C.sub.6 alkoxy, amino, mono- or di-alkylamino where each
alkyl is independently optionally substituted with amino, mono- or
dialkylamino, or R.sub.o is a group of the formula ##STR00184##
where p, D, D', and R.sub.z are as defined above; ##STR00185##
independently represent a carbon chain optionally substituted with
hydrogen, halogen, oxo, cyano, nitro, amino, mono or dialkylamino,
straight or branched chain alkyl, alkenyl, alkynyl,
trifluoromethyl, trifluoromethoxy, or cycloalkyl; wherein k is 0,
1, 2, or 3; m is 0, 1, 2, or 3; and R.sub.3, R.sub.4, R.sub.5, and
R.sub.6 are the same or different and are independently selected at
each occurrence from hydrogen, alkyl, --COR.sub.11 or
--CO.sub.2R.sub.11 where R.sub.11 is alkyl or cycloalkyl having 3-7
carbon atoms; or --CONR.sub.12R.sub.13 where R.sub.12 and R.sub.13
are selected independently from hydrogen, alkyl, cycloalkyl having
3-7 carbon atoms, phenyl, 2-, 3-, or 4-pyridyl, or
NR.sub.12R.sub.13 forms a heterocyclic group which is morpholinyl,
piperidinyl, pyrrolidinyl, or N-alkyl piperazinyl; or
R.sub.3-R.sub.4 are taken together to form a cyclic moiety having
3-7 carbon atoms; or R.sub.5-R.sub.6 are taken together to form a
cyclic moiety having 3-7 carbon atoms; where each alkyl group
forming an R.sub.3, R.sub.4, R.sub.5, or R.sub.6 substituent or
portion thereof may be substituted independently with hydroxy or
mono- or dialkylamino where each alkyl is independently alkyl or
cycloalkyl.
2. A compound according to claim 1, of the formula: ##STR00186##
wherein Y is independently selected at each occurrence from
hydrogen, hydroxy, halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy, cyano, nitro, amino, and mono- or
dialkyl(C.sub.1-C.sub.6)amino.
3. A compound according to claim 1, of the formula: ##STR00187##
wherein Y is independently selected at each occurrence from
hydroxy, halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
cyano, nitro, amino, and mono- or
dialkyl(C.sub.1-C.sub.6)amino.
4. A compound of the formula: ##STR00188## or a pharmaceutically
acceptable salt thereof wherein: T is halogen, hydrogen, hydroxyl,
amino, alkyl or alkoxy; X is hydrogen, hydroxy, amino, benzyl,
t-butoxycarbonyl, benzyloxycarbonyl, alkyl, or alkoxy; G represents
##STR00189## W is oxygen or methylene; Z is oxygen, nitrogen, or
methylene; m is 1 or 2; n is 0, 1, 2, or 3; and R.sub.3, R.sub.4,
R.sub.5, and R.sub.6 are the same or different and are
independently selected at each occurrence from hydrogen, alkyl,
--COR.sub.11 or --CO.sub.2R.sub.11 where R.sub.11 is alkyl or
cycloalkyl having 3-7 carbon atoms; or --CONR.sub.12R.sub.13 where
R.sub.12 and R.sub.13 are selected independently from hydrogen,
alkyl, cycloalkyl having 3-7 carbon atoms, phenyl, 2-, 3-, or
4-pyridyl, or NR.sub.12R.sub.13 forms a heterocyclic group which is
morpholinyl, piperidinyl, pyrrolidinyl, or N-alkyl piperazinyl; or
R.sub.3 and R.sub.4 together with the carbon atom to which they are
attached form a cyclic moiety having 3-7 carbon atoms; or R.sub.5
and R.sub.6 together with the carbon atom to which they are
attached form a cyclic moiety having 3-7 carbon atoms; where each
alkyl group forming an R.sub.3, R.sub.4, R.sub.5, or R.sub.6
substituent or portion thereof may be substituted independently
with hydroxy or mono- or dialkylamino where each alkyl is
independently alkyl or cycloalkyl.
5. A compound according to claim 4, of the formula:
##STR00190##
6. A compound according to claim 4, of the formula:
##STR00191##
7. A compound according to claim 4, of the formula:
##STR00192##
8. A compound according to claim 4, of the formula:
##STR00193##
9. A compound of the formula: ##STR00194## wherein: R is hydrogen
or alkyl wherein the alkyl is straight, branched, or cyclic, may
contain one or two double and/or triple bonds, and is unsubstituted
or substituted with one or more substituents selected from hydroxy,
oxo, halogen, amino, cyano, nitro, and alkoxy; each Y is
independently selected from hydrogen, hydroxy, halogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, cyano, nitro, amino,
and mono- or dialkyl(C.sub.1-C.sub.6)amino; T is halogen, hydrogen,
hydroxyl, amino, alkyl or alkoxy; X is hydrogen, hydroxy, amino,
benzyl, t-butoxycarbonyl, benzyloxycarbonyl, alkyl, or alkoxy; m is
1-3; and R.sub.3, R.sub.4, R.sub.5, and R.sub.6 are the same or
different and are independently selected at each occurrence from
hydrogen, alkyl, --COR.sub.11 or --CO.sub.2R.sub.11 where R.sub.11
is alkyl or cycloalkyl having 3-7 carbon atoms; or
--CONR.sub.12R.sub.13 where R.sub.12 and R.sub.13 are selected
independently from hydrogen, alkyl, cycloalkyl having 3-7 carbon
atoms, phenyl, 2-, 3-, or 4-pyridyl, or NR.sub.12R.sub.13 forms a
heterocyclic group which is morpholinyl, piperidinyl, pyrrolidinyl,
or N-alkyl piperazinyl; or R.sub.3 and R.sub.4 together with the
carbon atom to which they are attached form a cyclic moiety having
3-7 carbon atoms; or R.sub.5 and R.sub.6 together with the carbon
atom to which they are attached form a cyclic moiety having 3-7
carbon atoms; where each alkyl group forming an R.sub.3, R.sub.4,
R.sub.5, or R.sub.6 substituent or portion thereof may be
substituted independently with hydroxy or mono- or dialkylamino
where each alkyl is independently alkyl or cycloalkyl.
10. A compound according to claim 9, of the formula: ##STR00195##
where R.sub.3, R.sub.5, and R.sub.6 independently represent
hydrogen or alkyl; R.sub.a represents hydrogen or alkyl where the
alkyl is optionally halogenated; and e is an integer of 1-3.
11. A compound according to claim 9, of the formula: ##STR00196##
wherein: R.sub.a and R.sub.b are independently hydrogen or alkyl
wherein each alkyl is independently straight, branched, or cyclic,
may contain one or two double or triple bonds, and is unsubstituted
or substituted with one or more substitutents selected from:
hydroxy, oxo, halogen, amino, cyano, nitro, and alkoxy; or R.sub.a
and R.sub.b are joined to form a heterocycloalkyl ring; and Y is
independently selected at each occurrence from hydrogen, hydroxy,
halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, cyano,
nitro, amino, and mono- or dialkyl(C.sub.1-C.sub.6)amino.
12. A compound of the formula: ##STR00197## where R.sub.3, R.sub.5,
and R.sub.6 independently represent hydrogen, or alkyl; R.sub.a
represents hydrogen or alkyl where the alkyl is optionally
halogenated; T is halogen, hydrogen, hydroxyl, amino, alkyl or
alkoxy; and e is an integer of 1-3.
13. A compound according to claim 4, of the formula: ##STR00198##
where G represents: ##STR00199## where V is oxygen, nitrogen, or
methylene; and m is 1 or 2.
14. A compound which is
N-[4-(2-Pyrrolidinylethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-c-
arboxamide; or
N-{3-[2-(3-Trifluoromethylbenzylamino)ethoxy]phenyl}-4-oxo-4,5,6,7-tetrah-
ydro-1H-indole-3-carboxamide.
15. A compound which is
N-{3-[3-(3-Trifluoromethylbenzylamino)propoxy]phenyl}-4-oxo-4,5,6,7-tetra-
hydro-1H-indole-3-carboxamide;
N-[4-(2-Pyrrolidin-1-ylethyl)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-
-carboxamide;
N-[2-Fluoro-4-(2-n-propylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H--
indole-3-carboxamide; or
N-[3-Fluoro-4-(2-n-propylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H--
indole-3-carboxamide.
16. A compound according to claim 1 which is
N-[3-Fluoro-4-(2-n-propylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H--
indole-3-carboxamide hydrochloride;
N-[3-Fluoro-4-(2-Cyclopropylmethylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetra-
hydro-1H-indole-3-carboxamide; or
N-[3-Fluoro-4-(2-Cyclopropylmethylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetra-
hydro-1H-indole-3-carboxamide tosylate.
17. A compound which is
N-[3-Fluoro-4-(2-Isobutylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H--
indole-3-carboxamide;
N-[3-Fluoro-4-(2-n-butylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-i-
ndole-3-carboxamide;
N-[3-Fluoro-4-(2-t-butylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-i-
ndole-3-carboxamide;
N-[4-(2-adamant-2-ylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-
e-3-carboxamide;
N-{4-[(R)-Pyrrolidin-2-ylmethoxy]phenyl}-4-oxo-4,5,6,7-tetrahydro-1H-indo-
le-3-carboxamide;
N-{4-[(S)-Pyrrolidin-2-ylmethoxy]phenyl}-4-oxo-4,5,6,7-tetrahydro-1H-indo-
le-3-carboxamide; or
N-[4-(Piperidin-3-ylmethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3--
carboxamide.
18. A compound which is
N-[4-(Piperidin-3-ylmethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3--
carboxamide hydrochloride;
N-[3-Fluoro-4-(2-dimethylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H--
indole-3-carboxamide;
N-[4-(2-Pyrrolidin-1-ylethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole--
3-carboxamide;
N-[3-Fluoro-4-(2-pyrrolidin-1-ylethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1-
H-indole-3-carboxamide;
N-[4-(2-Piperidin-2-ylethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-
-carboxamide;
N-{4-[3-(2,2,2,-Trifluorethyl)aminopropoxy]phenyl}-4-oxo-4,5,6,7-tetrahyd-
ro-1H-indole-3-carboxamide; or N-{4-[2-(4-Methylaminopiperizin-1
yl)-2-oxo-ethyl]phenyl}-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide.
19. A compound according to claim 1, which is
N-[3-Fluoro-4-(2-hydroxy-2-oxoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H--
indole-3-carboxamide;
N-[3-Fluoro-4-(2-ethylamino-2-oxoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro--
1H-indole-3-carboxamide;
N-[3-Fluoro-4-(2-diethylamino-2-oxoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydr-
o-1H-indole-3-carboxamide; or
N-{3-Fluoro-4-[2-(4-methylpiperizin-1-yl)-2-oxoethoxy]phenyl}-4-oxo-4,5,6-
,7-tetrahydro-1H-indole-3-carboxamide.
20. A compound which is
N-ethyl-N-[2-(ethylamino)ethyl]-2-{4-[(4-oxo-(4,5,6,7-tetrahydroindol-3-y-
l))carbonylamino]phenoxy}acetamide;
N-[2-(dipropylamino)ethyl]-2-{4-[(4-oxo-(4,5,6,7-tetrahydroindol-3-yl))ca-
rbonylamino]phenoxy}acetamide;
N-[2-(diethylamino)ethyl]-N-methyl-2-{4-[(4-oxo-(4,5,6,7-tetrahydroindol--
3-yl))carbonylamino]phenoxy}acetamide;
N-[2-(diethylamino)ethyl]-N-ethyl-2-{4-[(4-oxo-(4,5,6,7-tetrahydroindol-3-
-yl))carbonylamino]phenoxy}acetamide;
N-[3-fluoro-4-(2-morpholin-4-yl-2-oxoethoxy)phenyl](4-oxo-(4,5,6,7-tetrah-
ydroindol-3-yl))carboxamide;
(4-oxo-(4,5,6,7-trihydroindol-3-yl))-N-[4-(2-oxo-2-piperazinylethoxy)phen-
yl]carboxamide;
N-[3-(diethylamino)propyl]-2-{4-[(4-oxo-(4,5,6,7-tetrahydroindol-3-yl))ca-
rbonylamino]phenoxy}acetamide;
N-[3-(diethylamino)propyl]-2-{2-fluoro-4-[(4-oxo-(4,5,6,7-tetrahydroindol-
-3-yl))carbonylamino]phenoxy}acetamide; or
N-[4-(diethylamino)-1-methylbutyl]-2-{4-[(4-oxo-(4,5,6,7-tetrahydroindol--
3-yl))carbonylamino]phenoxy}acetamide.
21. A compound of the formula: ##STR00200## or the pharmaceutically
acceptable non-toxic salts thereof wherein: Q is phenyl which may
be mono or disubstituted with hydroxy or halogen; T is halogen,
hydrogen, hydroxyl, amino, alkyl or alkoxy; W is oxygen or
nitrogen; Z is C.sub.3-C.sub.7 azacycloalkyl, --O(C.sub.1-C.sub.6
alkyl.sub.1), --S(O).sub.0-2(C.sub.1-C.sub.6 alkyl.sub.1),
--C(.dbd.O) (C.sub.1-C.sub.6 alkyl.sub.1), --OC(.dbd.O)
(C.sub.1-C.sub.6 alkyl.sub.1), --OC(.dbd.O)H,
--C(.dbd.O)O(C.sub.1-C.sub.6 alkyl.sub.1), --C(.dbd.O)OH,
--C(.dbd.O)NH(C.sub.1-C.sub.6 alkyl.sub.1), --C(.dbd.O)NH.sub.2,
--NHC(.dbd.O) (C.sub.1-C.sub.6 alkyl.sub.1), --NHC(.dbd.O)H,
--N(C.sub.1-C.sub.6 alkyl.sub.1)C(.dbd.O) (C.sub.1-C.sub.6
alkyl.sub.1), --NHS(O).sub.0-2(C.sub.1-C.sub.6 alkyl.sub.1),
--N(C.sub.1-C.sub.6 alkyl.sub.1)S(O).sub.0-2(C.sub.1-C.sub.6
alkyl.sub.1), --S(O).sub.0-2NH(C.sub.1C.sub.6 alkyl.sub.1), or
--S(O).sub.0-2(C.sub.1-C.sub.6 alkyl.sub.1)N(C.sub.1-C.sub.6
alkyl.sub.1), wherein C.sub.1-C.sub.6 alkyl.sub.1 is independently
chosen at each occurrence and is straight, branched, or cyclic, may
contain one or two double or triple bonds, and is unsubstituted or
substituted with one or more substitutents selected from: hydroxy,
oxo, halogen, amino, cyano, nitro, and alkoxy, or Z is phenyl or
phenyl(C.sub.1-C.sub.6)alkyl where the phenyl portion is optionally
substituted with C.sub.1-C.sub.6 alkyl, hydroxy, C.sub.1-C.sub.6
alkoxy, trifluoromethyl, trifluoromethoxy, halogen, amino, or mono-
or diC.sub.1-C.sub.6 alkylamino, or Z represents a group of the
formula: ##STR00201## where p is 1, 2, or 3; D and D' independently
represent oxygen, NR.sub.y or CHR.sub.y provided that only one of D
and D' may be NR.sub.y where each R.sub.y is hydrogen or
C.sub.1-C.sub.6 alkyl; or and R.sub.z is hydrogen or
C.sub.1-C.sub.6 alkyl, or Z represents a group of the formula:
##STR00202## where p is 1, 2, or 3; q is 0, 1, or 2; R.sub.z is
hydrogen or C.sub.1-C.sub.6 alkyl; or Z is a group of the formula:
##STR00203## where s is 0, 1, 2 or 3, and the sum of s and m is not
less than 1; R.sub.o is hydroxy, C.sub.1-C.sub.6 alkoxy, amino,
mono- or diC.sub.1-C.sub.6 alkylamino where each alkyl is
independently optionally substituted with amino, mono- or
diC.sub.1-C.sub.6 alkylamino, or R.sub.o is a group of the formula
##STR00204## where p, D, D', and R.sub.z are as defined above;
##STR00205## independently represent a carbon chain optionally
substituted with hydrogen, halogen, oxo, cyano, nitro, amino, mono
or di(C.sub.1-C.sub.6)alkylamino, straight or branched chain
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, trifluoromethyl, trifluoromethoxy, or cycloC.sub.1-C.sub.6
alkyl; wherein k is 0, 1, 2, or 3; m is 0, 1, 2, or 3; and
##STR00206## represents a carbon chain optionally substituted with
R.sub.5 and R.sub.6 and n is 0, 1, 2, or 3; R.sub.3, R.sub.4,
R.sub.5, and R.sub.6 are the same or different and are
independently selected at each occurrence from hydrogen,
C.sub.1-C.sub.6 alkyl, --COR.sub.11 or --CO.sub.2R.sub.11 where
R.sub.11 is C.sub.1-C.sub.6 alkyl or C.sub.3-C.sub.7 cycloalkyl; or
--CONR.sub.12R.sub.13 where R.sub.12 and R.sub.13 are selected
independently from hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7
cycloalkyl, phenyl, 2-, 3-, or 4-pyridyl, or NR.sub.12R.sub.13
forms a heterocyclic group which is morpholinyl, piperidinyl,
pyrrolidinyl, or N-alkyl piperazinyl; or R.sub.3-R.sub.4 are taken
together to form a cyclic moiety having 3-7 carbon atoms; or
R.sub.5-R.sub.6 are taken together to form a cyclic moiety having
3-7 carbon atoms; and where each alkyl group forming an R.sub.3,
R.sub.4, R.sub.5, or R.sub.6 substitutent or portion thereof may be
substituted independently with hydroxy or mono- or dialkylamino
where each alkyl is independently C.sub.3-C.sub.7 alkyl or
cycloalkyl having 3-7 carbon atoms.
22. A compound of formula A: ##STR00207## or a pharmaceutically
acceptable salt thereof wherein R.sub.3, R.sub.4, R.sub.5, and
R.sub.6 are the same or different and are selected from hydrogen,
alkyl, --COR.sub.11 or --CO.sub.2R.sub.11 where R.sub.11 is alkyl
or cycloalkyl having 3-7 carbon atoms; or --CONR.sub.12R.sub.13
where R.sub.12 and R.sub.13 are selected independently from
hydrogen, alkyl, cycloalkyl having 3-7 carbon atoms, phenyl, 2-,
3-, or 4-pyridyl, or NR.sub.12R.sub.13 forms a heterocyclic group
which is morpholinyl, piperidinyl, pyrrolidinyl, or N-alkyl
piperazinyl; or R.sub.3-R.sub.4 are taken together to form a cyclic
moiety having 3-7 carbon atoms; or R.sub.5-R.sub.6 are taken
together to form a cyclic moiety having 3-7 carbon atoms; and where
each alkyl group forming an R.sub.3, R.sub.4, R.sub.5, or R.sub.6
substituent or portion thereof may be substituted independently
with hydroxy or mono- or dialkylamino where each alkyl is
independently alkyl or cycloalkyl having 3-7 carbon atoms; and G
represents ##STR00208## where R.sub.h is hydorgen, halogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, or trifluoromethyl;
s is 0, 1, 2 or 3, and the sum of s and m is not less than 1;
R.sub.o is hydroxy, C.sub.1-C.sub.6 alkoxy, amino, mono- or
diC.sub.1-C.sub.6 alkylamino where each alkyl is independently
optionally substituted with amino, mono- or diC.sub.1-C.sub.6
alkylamino, or R.sub.o is a group of the formula ##STR00209## p is
1, 2, or 3; D and D' independently represent oxygen, NR.sub.y or
CHR.sub.y provided that only one of D and D' may be NR.sub.y where
each R.sub.y is hydrogen or C.sub.1-C.sub.6 alkyl; or and R.sub.z
is hydrogen or C.sub.1-C.sub.6 alkyl.
23. A compound according to claim 22, wherein R.sub.h is hydrogen
or halogen, and R.sub.o is a group of the formula: ##STR00210##
where R.sub.14 is hydrogen or C.sub.1-C.sub.6 alkyl; R.sub.15 is
hydrogen or C.sub.1-C.sub.6 alkyl; R.sub.16 is hydrogen, ethyl, or
methyl; R.sub.17 is C.sub.1-C.sub.6 alkyl; and J is a
C.sub.1-C.sub.4 alkylene group.
24. A compound according to claim 22, wherein s is 1 and R.sub.o is
ethoxy, hydroxy, ethylamino, diethylamino, morpholinyl,
piperazinyl, 4-methylpiperazinyl, ##STR00211##
25. A pharmaceutical composition comprising a compound according to
claim 4 combined with at least one pharmaceutically acceptable
carrier or excipient.
26. A method for the treatment of a disease or disorder associated
with pathogenic agonism, inverse agonism or antagonism of the
GABA.sub.A receptor, said method comprising administering to a
patient in need of such treatment an effective amount of a compound
of claim 4.
27. A method according to claim 26 wherein the disease or disorder
associated with pathogenic agonism, inverse agonism or antagonism
of the GABA.sub.A receptor is anxiety, depression, a sleep
disorder, or cognitive impairment.
28. A method for localizing GABA.sub.A receptors in a tissue sample
comprising contacting with the sample a detectably-labeled compound
of claim 4 under conditions that permit binding of the compound to
GABA.sub.A receptors, washing the sample to remove unbound
compound, and detecting the bound compound.
29. A method of inhibiting the binding of a benzodiazepine compound
to a GABA.sub.A receptor, said method comprising contacting a
compound of claim 4 with cells expressing such a receptor in the
presence of the benzodiazepine, wherein the compound is present at
a concentration sufficient to inhibit the binding a benzodiazepine
compound to a GABA.sub.A receptor in vitro.
30. A packaged pharmaceutical composition comprising the
pharmaceutical composition of claim 4 in a container and
instructions for using the composition to treat a patient suffering
from a disorder responsive to agonism, inverse agonism or
antagonism of the GABA.sub.A receptor.
31. The packaged pharmaceutical composition of claim 30, wherein
said patient is suffering from anxiety, depression, a sleep
disorder, cognitive impairment, or Alzheimer's dementia.
32. A compound of the formula: ##STR00212## wherein Y is halogen; m
is 1, 2 or 3; and Z is amino or mono or dialkylamino.
33. A compound according to claim 32 wherein Z is monoalkylamino, m
is 2, and Y is fluorine.
34. A compound of the formula: ##STR00213## wherein Y is hydrogen,
halogen or hydroxy; m is 1, 2 or 3; and Z is amino or mono or
dialkylamino.
35. A compound according to claim 10 wherein n is 1.
36. A method for altering the signal-transducing activity of
GABA.sub.A receptors, said method comprising exposing cells
expressing such receptors to a compound according to claim 4 at a
concentration sufficient to inhibit RO15-1788 binding to cells
expressing a cloned human GABA.sub.A receptor in vitro.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to fused pyrrolecarboxamides. This invention
also relates to pharmaceutical compositions comprising such
compounds and to the use of such compounds in treatment of certain
central nervous system (CNS) diseases. This invention also relates
to the use of these fused pyrrolecarboxamide compounds in
combination with one or more other CNS agents to potentiate the
effects of the other CNS agents. Additionally this invention
relates to the use such compounds as probes for the localization of
GABA.sub.A receptors in tissue sections.
2. Description of the Related Art
The GABA.sub.A receptor superfamily represents one of the classes
of receptors through which the major inhibitory neurotransmitter,
.gamma.-aminobutyric acid, or GABA, acts. Widely, although
unequally, distributed through the mammalian brain, GABA mediates
many of its actions through a complex of proteins called the
GABA.sub.A receptor, which causes alteration in chloride
conductance and membrane polarization.
A number of cDNAs for GABA.sub.A receptor subunits have been
characterized. To date at least 6.alpha., 3.beta., 3.gamma.,
1.epsilon., 1.delta. and 2.rho. subunits have been identified. It
is generally accepted that native GABA.sub.A receptors are
typically composed of 2.alpha., 2.beta., and 1.gamma. subunits
(Pritchett & Seeburg Science 1989; 245:1389-1392 and Knight et.
al., Recept. Channels 1998; 6:1-18). Evidence such as message
distribution, genome localization and biochemical study results
suggest that the major naturally occurring receptor combinations
are .alpha..sub.1.beta..sub.2.gamma..sub.2,
.alpha..sub.2.beta..sub.3.gamma..sub.2,
.alpha..sub.3.beta..sub.3.gamma..sub.2, and
.alpha..sub.5.beta..sub.3.gamma..sub.2 (Mohler et. al. Neuroch.
Res. 1995; 20(5): 631-636).
Benzodiazepines exert their pharmacological actions by interacting
with the benzodiazepine binding sites associated with the
GABA.sub.A receptor. In addition to the benzodiazepine site, the
GABA.sub.A receptor contains sites of interaction for several other
classes of drugs. These include a steroid binding site, a
picrotoxin site, and the barbiturate site. The benzodiazepine site
of the GABA.sub.A receptor is a distinct site on the receptor
complex that does not overlap with the site of interaction for GABA
or for other classes of drugs that bind to the receptor (see, e.g.,
Cooper, et al., The Biochemical Basis of Neuropharmacology,
6.sup.th ed., 1991, pp. 145-148, Oxford University Press, New
York). Early electrophysiological studies indicated that a major
action of the benzodiazepines was enhancement of GABAergic
inhibition. Compounds that selectively bind to the benzodiazepine
site and enhance the ability of GABA to open GABA.sub.A receptor
channels are agonists of GABA receptors. Other compounds that
interact with the same site but negatively modulate the action of
GABA are called inverse agonists. Compounds belonging to a third
class bind selectively to the benzodiazepine site and yet have
little or no effect on GABA activity, but can block the action of
GABA.sub.A receptor agonists or inverse agonists that act at this
site. These compounds are referred to as antagonists.
The important allosteric modulatory effects of drugs acting at the
benzodiazepine site were recognized early and the distribution of
activities at different receptor subtypes has been an area of
intense pharmacological discovery. Agonists that act at the
benzodiazepine site are known to exhibit anxiolytic, sedative, and
hypnotic effects, while compounds that act as inverse agonists at
this site elicit anxiogenic, cognition enhancing, and proconvulsant
effects. While benzodiazepines have a long history of
pharmaceutical use as anxiolytics, these compounds often exhibit a
number of unwanted side effects. These may include cognitive
impairment, sedation, ataxia, potentiation of ethanol effects, and
a tendency for tolerance and drug dependence.
GABA.sub.A selective ligands may also act to potentiate the effects
of certain other CNS active compounds. For example, there is
evidence that selective serotonin reuptake inhibitors (SSRIs) may
show greater antidepressant activity when used in combination with
GABA.sub.A selective ligands than when used alone.
Various compounds have been prepared as benzodiazepine agonists and
antagonists. For Example, U.S. Pat. Nos. 3,455,943, 4,435,403,
4,596,808, 4,623,649, and 4,719,210, German Patent No. DE
3,246,932, and Liebigs Ann. Chem. 1986, 1749 teach assorted
benzodiazepine agonists and antagonists and related anti-depressant
and central nervous system active compounds.
U.S. Pat. No. 3,455,943 disclosed indole derivatives.
Other references, such as U.S. Pat. No. 4,435,403 and German patent
DE 3,246,932 disclose pyrimidino[5,4-b]indoles and beta-carboline
derivatives.
A variety of indole-3-carboxamides is described in the literature.
See, for example, J. Org. Chem., 42: 1883-1885 (1977); J.
Heterocylic Chem., 14: 519-520 (1977). Also, U.S. Pat. Nos.
5,804,686 and 6,080,873 and PCT International Publication WO
97/26243, all of which are assigned to Neurogen Corporation,
disclose fused pyrrolecarboxamides.
SUMMARY OF THE INVENTION
In a preferred aspect, this invention provides pyrrolecarboxamides
that bind with high affinity and high selectivity to the
benzodiazepine site of the GABA.sub.A receptor, including human
GABA.sub.A receptors.
Thus, the invention provides compounds of Formula I (shown below),
and pharmaceutical compositions comprising compounds of Formula
I.
The invention further comprises methods of treating patients
suffering from CNS disorders with an effective amount of a compound
of the invention. The patient may be a human or other mammal.
Treatment of humans, domesticated companion animals (pet) or
livestock animals suffering from CNS disorders with an effective
amount of a compound of the invention is encompassed by the
invention.
In a separate aspect, the invention provides a method of
potentiating the actions of other CNS active compounds. This method
comprises administering an effective amount of a compound of the
invention with another CNS active compound.
Additionally this invention relates to the use of the compounds of
the invention as probes for the localization of GABA.sub.A
receptors in tissue sections.
Accordingly, a broad aspect of the invention is directed to
compounds of the formula ##STR00001## or the pharmaceutically
acceptable salts thereof wherein: T is halogen, hydrogen, hydroxyl,
amino, alkyl or alkoxy; X is hydrogen, hydroxy, amino, benzyl,
t-butoxycarbonyl, benzyloxycarbonyl, alkyl, or alkoxy; G represents
##STR00002## where Q is an optionally substituted aryl or
optionally substituted heteroaryl group having from 1 to 3 rings, 3
to 8 members in each ring and from 1 to 3 heteroatoms; W is chosen
from hydrogen, --O--, --NH--, --NR.sub.7--, --S(O).sub.0-2--,
--C(.dbd.O)--, --OC(.dbd.O)--, --C(.dbd.O)O--, --C(.dbd.O)NH--,
--NHC(.dbd.O)--, --NR.sub.7C(.dbd.O)--, --NHS(O).sub.0-2--,
--NR.sub.7S(O).sub.0-2--, --S(O).sub.0-2NH--,
--S(O).sub.0-2NR.sub.7--, and CR.sub.7R.sub.8 where R.sub.7 and
R.sub.8 are the same or different and represent hydrogen, alkyl, or
CR.sub.7R.sub.8 represents a cyclic moiety having 3-7 carbon atoms,
wherein W may not be hydrogen when Q is phenyl, 2- or 3-thienyl, or
2-, 3-, or 4 pyridyl, indolyl, imidazolyl, or pyridazinyl; Z is
hydrogen, hydroxy, cycloalkyl(alkoxy), amino, mono- or
di(alkyl.sub.1)amino, azacycloalkyl, --O(alkyl.sub.1),
--S(O).sub.0-2(alkyl.sub.1), --C(.dbd.O)(alkyl.sub.1),
--OC(.dbd.O)(alkyl.sub.1), --OC(.dbd.O)H,
--C(.dbd.O)O(alkyl.sub.1), --C(.dbd.O)OH,
--C(.dbd.O)NH(alkyl.sub.1), --C(.dbd.O)N(alkyl.sub.1).sub.2,
--C(.dbd.O)NH.sub.2, --NHC(.dbd.O)(alkyl.sub.1), --NHC(.dbd.O)H,
--N(alkyl.sub.1)C(.dbd.O)(alkyl.sub.1),
--NHS(O).sub.0-2(alkyl.sub.1),
--N(alkyl.sub.1)S(O).sub.0-2(alkyl.sub.1),
--S(O).sub.0-2NH(alkyl.sub.1),
--S(O).sub.0-2(alkyl.sub.1)N(alkyl.sub.1), wherein each alkyl.sub.1
is independently straight, branched, or cyclic, may contain one or
two double and/or triple bonds or combinations thereof, and is
unsubstituted or substituted with one or more substituents
independently selected from hydroxy, oxo, halogen, amino, cyano,
nitro, and alkoxy, or Z is --N(R.sub.N).sub.2S(O).sub.0-2(R.sub.S)
where each R.sub.N is independently hydrogen or alkyl where the
alkyl is straight, branched, or cyclic, may contain one or two
double and/or triple bonds, and is unsubstituted or substituted
with one or more substituents independently selected from hydroxy,
oxo, halogen, amino, cyano, nitro, and alkoxy, R.sub.S is hydroxy,
alkoxy, heteroaryl, aryl, or alkyl where each aryl and heteroaryl
is optionally substituted with one or two of alkyl, hydroxy,
alkoxy, trifluoromethyl, halogen, amino, or mono- or dialkylamino;
and each alkyl is optionally substituted with hydroxy, alkoxy,
trifluoromethyl, halogen, amino, mono- or di-alkylamino, aryl, or
heteroaryl; or Z is phenyl or phenylalkyl where the phenyl portion
is optionally substituted with alkyl, hydroxy, alkoxy,
trifluoromethyl, halogen, amino, or mono- or dialkylamino, or Z is
2-, 3-, or 4-pyridyl, 1- or 2-imidazolyl, 1-, 2-, or 3-pyrrolyl,
azeditinyl, norborn-2-yl, or adamantan-2-yl; each of which may be
substituted on a tertiary carbon or a secondary nitrogen with
C.sub.1-C.sub.6alkyl, or Z is NR.sub.9COR.sub.10 where R.sub.9 and
R.sub.10 are the same or different and represent hydrogen or alkyl
or cycloalkyl, or Z is connected, optionally through W, to Q to
form a 1-6 membered ring; or Z represents a group of the formula:
##STR00003## where p is 1, 2, or 3; D and D' independently
represent oxygen, NR.sub.y or CHR.sub.y provided that only one of D
and D' may be NR.sub.y, and only one of D and D' may be oxygen,
where each R.sub.y is hydrogen or alkyl; and R.sub.z is hydrogen or
alkyl, or Z represents a group of the formula: ##STR00004## where p
is 1, 2, or 3; q is 0, 1, or 2; each R.sub.z is independently
hydrogen or alkyl; or Z represents a group of the formula:
##STR00005## where s is 0, 1, 2 or 3, and the sum of s and m is not
less than 1; R.sub.o is hydroxy, C.sub.1-C.sub.6alkoxy, amino,
mono- or dialkylamino where each alkyl is independently optionally
substituted with amino, or mono- or dialkylamino, or R.sub.o is a
group of the formula ##STR00006## where p, D, D', and R.sub.z are
as defined above; ##STR00007## independently represent a carbon
chain optionally substituted with halogen, oxo, cyano, nitro,
amino, mono or dialkylamino, alkyl, alkenyl, alkynyl,
trifluoromethyl, trifluoromethoxy, or cycloalkyl; wherein k is 0,
1, 2, or 3; m is 0, 1, 2, or 3; and ##STR00008## represents a
carbon chain optionally substituted with R.sub.5 and R.sub.6 and n
is 0, 1, 2, or 3; and R.sub.3, R.sub.4, R.sub.5, and R.sub.6 are
the same or different and are independently selected at each
occurrence from hydrogen, alkyl, --COR.sub.11 or --CO.sub.2R.sub.11
where R.sub.11 is alkyl or cycloalkyl having 3-7 carbon atoms; or
--CONR.sub.12R.sub.13 where R.sub.12 and R.sub.13 are selected
independently from hydrogen, alkyl, cycloalkyl having 3-7 carbon
atoms, phenyl, 2-, 3-, or 4-pyridyl, or NR.sub.12R.sub.13 forms a
heterocyclic group which is morpholinyl, piperidinyl, pyrrolidinyl,
or N-alkyl piperazinyl; or R.sub.3 and R.sub.4 together with the
carbon atom to which they are attached form a cyclic moiety having
3-7 carbon atoms; or R.sub.5 and R.sub.6 together with the carbon
atom to which they are attached form a cyclic moiety having 3-7
carbon atoms; where each alkyl group forming an R.sub.3, R.sub.4,
R.sub.5, or R.sub.6 substituent or portion thereof may be
substituted independently with hydroxy or mono- or dialkylamino
where each alkyl is independently alkyl or cycloalkyl.
In another aspect, the invention provides intermediates useful for
preparing compounds of Formula I.
DETAILED DESCRIPTION OF THE INVENTION
In addition to compounds of Formula I described above, the
invention also encompasses compounds of the same general formula
and the pharmaceutically acceptable salts thereof, wherein: T is
halogen, hydrogen, hydroxyl, C.sub.1-C.sub.6 amino, alkyl or
C.sub.1-C.sub.6 alkoxy; X is hydrogen, hydroxy, amino,
C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 alkoxy; G represents
##STR00009## where Q is phenyl, 2- or 3-thienyl, or 2-, 3-, or 4
pyridyl, 2-, 4-, or 5-pyrimidinyl, indolyl, imidazolyl,
pyridazinyl, 1,4-benzodioxazinyl, 1,3-benzodioxolyl or
imidazo[1,2-a]pyridinyl, all of which may be substituted by one or
more of hydroxy, halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy, cyano, nitro, amino, and mono- or
dialkyl(C.sub.1-C.sub.6)amino; W is chosen from hydrogen, --O--,
--NH--, --NR.sub.7--, --S(O).sub.0-2--, --C(.dbd.O)--,
--OC(.dbd.O)--, --C(.dbd.O)O--, --C(.dbd.O)NH--, --NHC(.dbd.O)--,
--NR.sub.7C(.dbd.O)--, --NHS(O).sub.0-2--,
--NR.sub.7S(O).sub.0-2--, --S(O).sub.0-2NH--,
--S(O).sub.0-2R.sub.7H--, and CR.sub.7R.sub.8 where R.sub.7 and
R.sub.8 are the same or different and represent hydrogen, alkyl, or
R.sub.7-R.sub.8 taken together represents a cyclic moiety having
3-7 carbon atoms, wherein W may not be hydrogen when Q is phenyl,
2- or 3-thienyl, or 2-, 3-, or 4 pyridyl, indolyl, imidazolyl, or
pyridazinyl; Z is hydrogen, hydroxy, C.sub.3-C.sub.7
cycloalkyl(C.sub.1-C.sub.6 alkoxy), amino, mono- or
di(C.sub.1-C.sub.6 alkyl.sub.1)amino, or C.sub.3-C.sub.7
azacycloalkyl, --O(C.sub.1-C.sub.6 alkyl.sub.1),
--S(O).sub.0-2(C.sub.1-C.sub.6 alkyl.sub.1), --C(.dbd.O)
(C.sub.1-C.sub.6 alkyl.sub.1), --OC(.dbd.O)(C.sub.1-C.sub.6
alkyl.sub.1), --OC(.dbd.O)H, --C(.dbd.O)O(C.sub.1-C.sub.6
alkyl.sub.1), --C(.dbd.O)OH, --C(.dbd.O)NH(C.sub.1-C.sub.6
alkyl.sub.1), --C(.dbd.O)NH.sub.2, --NHC(.dbd.O) (C.sub.1-C.sub.6
alkyl.sub.1), --NHC(.dbd.O)H, --N(C.sub.1-C.sub.6
alkyl.sub.1)C(.dbd.O) (C.sub.1-C.sub.6 alkyl.sub.1),
--NHS(O).sub.0-2(C.sub.1-C.sub.6 alkyl.sub.1), --N(C.sub.1-C.sub.6
alkyl.sub.1)S(O).sub.0-2(C.sub.1-C.sub.6 alkyl.sub.1),
--S(O).sub.0-2NH(C.sub.1-C.sub.6 alkyl.sub.1), or
--S(O).sub.0-2(C.sub.1-C.sub.6
alkyl.sub.1)N(C.sub.1-C.sub.6alkyl.sub.1), wherein C.sub.1-C.sub.6
alkyl.sub.1 is independently chosen at each occurrence and is
straight, branched, or cyclic, may contain one or two double and/or
triple bonds, and is unsubstituted or substituted with one or more
substituents selected from hydroxy, oxo, halogen, amino, cyano,
nitro, and alkoxy, or Z is --N(R.sub.N).sub.2S(O).sub.0-2(R.sub.S)
where each R.sub.N is independently hydrogen or alkyl where the
alkyl is straight, branched, or cyclic, may contain one or two
double and/or triple bonds, and is unsubstituted or substituted
with one or more substituents independently selected from hydroxy,
oxo, halogen, amino, cyano, nitro, and alkoxy, R.sub.S is hydroxy,
alkoxy, or alkyl where the alkyl is optionally substituted with
hydroxy, alkoxy, trifluoromethyl, halogen, amino, mono- or
dialkylamino, aryl or heteroaryl, Z is phenyl or
phenyl(C.sub.1-C.sub.6)alkyl where the phenyl portion is optionally
substituted with C.sub.1-C.sub.6 alkyl, hydroxy, C.sub.1-C.sub.6
alkoxy, trifluoromethyl, trifluoromethoxy, halogen, amino, or mono-
or diC.sub.1-C.sub.6 alkylamino, or Z is 2-, 3-, or 4-pyridyl, 1-
or 2-imidazolyl, 1-, 2-, or 3-pyrrolyl, or adamantane-2-yl; each of
which may be substituted on a tertiary carbon or a secondary
nitrogen with C.sub.1-C.sub.6alkyl, or Z is NR.sub.9COR.sub.10
where R.sub.9 and R.sub.10 are the same or different and represent
hydrogen or C.sub.1-C.sub.6 alkyl or C.sub.3-C.sub.7 cycloalkyl, or
Z is connected, optionally through W, to Q to from a 1-6 membered
ring; or Z represents a group of the formula: ##STR00010## where p
is 1, 2, or 3; D and D' independently represent oxygen, NR.sub.y or
CHR.sub.y provided that only one of D and D' may be NR.sub.y where
each R.sub.y is hydrogen or C.sub.1-C.sub.6 alkyl; or and R.sub.z
is hydrogen or C.sub.1-C.sub.6 alkyl, or Z represents a group of
the formula: ##STR00011## where p is 1, 2, or 3; q is 0, 1, or 2;
R.sub.z is hydrogen or C.sub.1-C.sub.6 alkyl; or a group of the
formula: ##STR00012## where s is 0, 1, 2 or 3, and the sum of s and
m is not less than 1; R.sub.o is hydroxy, C.sub.1-C.sub.6alkoxy,
amino, mono- or diC.sub.1-C.sub.6alkylamino where each alkyl is
independently optionally substituted with amino, mono- or
diC.sub.1-C.sub.6alkylamino, or R.sub.o is a group of the formula
##STR00013## where p, D, D', and R.sub.z are as defined above;
##STR00014## independently represent a carbon chain optionally
substituted with hydrogen, halogen, oxo, cyano, nitro, amino, mono
or di(C.sub.1-C.sub.6)alkylamino, straight or branched chain
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, trifluoromethyl, trifluoromethoxy, or cycloC.sub.1-C.sub.6
alkyl; wherein k is 0, 1, 2, or 3; m is 0, 1, 2, or 3; and
##STR00015## represents a carbon chain optionally substituted with
R.sub.5 and R.sub.6 and n is 0, 1, 2, or 3; R.sub.3, R.sub.4,
R.sub.5, and R.sub.6 are the same or different and are
independently selected at each occurrence from hydrogen,
C.sub.1-C.sub.6 alkyl, --COR.sub.11 or --CO.sub.2R.sub.11 where
R.sub.11 is C.sub.1-C.sub.6alkyl or C.sub.3-C.sub.7 cycloalkyl; or
--CONR.sub.12R.sub.13 where R.sub.12 and R.sub.13 are selected
independently from hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7
cycloalkyl, phenyl, 2-, 3-, or 4-pyridyl, or NR.sub.12R.sub.13
forms a heterocyclic group which is morpholinyl, piperidinyl,
pyrrolidinyl, or N-alkyl piperazinyl; or R.sub.3 and R.sub.4
together with the carbon atom to which they are attached form a
cyclic moiety having 3-7 carbon atoms; or R.sub.5 and R.sub.6
together with the carbon atom to which they are attached form a
cyclic moiety having 3-7 carbon atoms; and where each alkyl group
forming an R.sub.3, R.sub.4, R.sub.5, or R.sub.6 substituent or
portion thereof may be substituted independently with hydroxy or
mono- or dialkylamino where each alkyl is independently
C.sub.3-C.sub.7 alkyl or cycloalkyl having 3-7 carbon atoms.
Such compounds will be referred to as compounds of Formula Ia.
Particular compounds of the invention also include compounds of
Formula I where Q is phenyl or pyridyl (compounds of Formula Ib)
and compounds of Formula I where Q is phenyl or pyridyl; and either
the group ##STR00016## is substituted by oxo (compounds of Formula
Ic).
When W is hydrogen, m is 0 and Z is absent resulting in Q groups
that are optionally substituted with alkyl where the alkyl is
optionally substituted as defined above.
In addition, the present invention encompasses compounds of Formula
II: ##STR00017## and the pharmaceutically acceptable salts thereof:
wherein n, k, m, R.sub.3-R.sub.6, X, T, W, and Z are defined as for
Formula I; Q is phenyl or pyridyl substituted by up to 4 groups Y,
where Y is independently selected at each occurrence from hydrogen,
hydroxy, halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
cyano, nitro, amino, and mono- or dialkyl(C.sub.1-C.sub.6)amino.
Compounds of Formula II, include compounds of Formula IIa, Formula
IIb, Formula IIc, and Formula IId shown below ##STR00018##
The present invention also encompasses compounds of Formula III
##STR00019## and the pharmaceutically acceptable salts thereof:
wherein n, k, m, R.sub.3-R.sub.6, X, T, W, and Z are defined as for
Formula I; Q is phenyl or pyridyl substituted by up to 4 groups Y,
where Y is independently selected at each occurrence from hydrogen,
hydroxy, halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
cyano, nitro, amino, and mono- or dialkyl(C.sub.1-C.sub.6)amino.
Particular compounds of Formula III include compounds of Formula
IIIa and Formula IIIb shown below. ##STR00020##
The present invention also encompasses compounds of Formula IV
##STR00021## and the pharmaceutically acceptable salts thereof:
wherein n, m, R.sub.3-R.sub.6, X, T, W, and Z are defined as for
Formula I; Q is phenyl or pyridyl substituted by up to 4 groups Y,
where Y is independently selected at each occurrence from hydrogen,
hydroxy, halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
cyano, nitro, amino, and mono- or dialkyl(C.sub.1-C.sub.6)amino.
Particularly included as compounds of Formula IV are compounds of
Formula IV-1, Formula IV-2, and Formula IV-3, shown below.
##STR00022##
Preferred compounds of Formula IV, IV-1, IV-2, and IV-3 are those
compounds where Z is a group --OR and R is hydrogen or alkyl
wherein the alkyl is straight, branched, or cyclic, may contain one
or two double and/or triple bonds, and is unsubstituted or
substituted with one or more substituents selected from: hydroxy,
oxo, halogen, amino, cyano, nitro, and alkoxy.
Other preferred compounds of Formula IV, IV-1, IV-2, and IV-3 are
those compounds where Z is a group --NR.sub.aR.sub.b wherein
R.sub.a and R.sub.b are independently hydrogen or alkyl wherein
each alkyl is independently straight, branched, or cyclic, may
contain one or two double and/or triple bonds, and is unsubstituted
or substituted with one or more substituents selected from:
hydroxy, oxo, halogen, amino, cyano, nitro, and alkoxy; or R.sub.a
and R.sub.b may be joined to form a heterocycloalkyl ring.
Further included as compounds of Formula IV are compounds of
Formula IVa and IVb: ##STR00023##
The present invention also encompasses compounds of Formula V.
##STR00024## wherein n, m, R.sub.3-R.sub.6, X, T, W, and Z are
defined as for Formula I; Q is phenyl or pyridyl substituted by up
to 4 groups Y, where Y is independently selected at each occurrence
from hydrogen, hydroxy, halogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, cyano, nitro, amino, and mono- or
dialkyl(C.sub.1-C.sub.6)amino. Particularly included as compounds
of Formula V are compounds of Formula Va, Formula Vb
##STR00025##
Especially preferred compounds of Formula V, Va, Vb, and Vc are
compounds of wherein Z is a groups --NR.sub.aR.sub.b wherein
R.sub.a and R.sub.b are independently hydrogen or alkyl wherein
each alkyl is independently straight, branched, or cyclic, may
contain one or two double and/or triple bonds, and is unsubstituted
or substituted with one or more substituents selected from:
hydroxy, oxo, halogen, amino, cyano, nitro, and alkoxy; or R.sub.a
and R.sub.b may be joined to form a heterocycloalkyl ring.
The present invention also encompasses compounds of Formula VI.
##STR00026## and the pharmaceutically acceptable salts thereof:
wherein n, m, R.sub.3-R.sub.6, X, T, and Z are defined as for
Formula I; Q is phenyl or pyridyl substituted by up to 4 groups Y,
where Y is independently selected at each occurrence from hydrogen,
hydroxy, halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
cyano, nitro, amino, and mono- or dialkyl(C.sub.1-C.sub.6)amino.
Particularly included as compounds of Formula VI are compounds of
Formula VIa and Formula VIb (shown below). ##STR00027## The present
invention also encompasses compounds of Formula VII. ##STR00028##
wherein W, Z, m, n, R.sub.3, R.sub.4, R.sub.5, and R.sub.6 are
defined as for Formula I.
The present invention also encompasses compounds of Formula VIII.
##STR00029## wherein W, Z, m, n, R.sub.3, R.sub.4, R.sub.5, and
R.sub.6 are defined for Formula I.
The present invention also encompasses compounds of Formula IX.
##STR00030## wherein W, Z, k, m, n, R.sub.3, R.sub.4, R.sub.5, and
R.sub.6 are defined as for Formula I.
The present invention also encompasses compounds of Formula X.
##STR00031## wherein W, Z, k, m, n, R.sub.3, R.sub.4, R.sub.5, and
R.sub.6 are defined as for Formula I.
Preferred compounds of the invention are those where n is 1 or 2.
Particularly preferred are those where X and T are both hydrogen.
Thus, preferred compounds of the invention have formulas A1 or B1.
##STR00032##
Preferred compounds of Formulas A1 and B1 are those where R.sub.3,
R.sub.4, R.sub.5 and R.sub.6 are independently hydrogen or alkyl.
More preferably, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are
independently hydrogen, methyl, or ethyl. Even more preferably,
R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are hydrogen or methyl, where
not more than 2 of R.sub.3-R.sub.6 are methyl. Particularly
preferred are compounds where R.sub.3 and R.sub.4 are
C.sub.1-C.sub.3 alkyl, most preferably methyl, when R.sub.5 and
R.sub.6 are hydrogen or where R.sub.5 and R.sub.6 are
C.sub.1-C.sub.3 alkyl, most preferably methyl, when R.sub.3 and
R.sub.4 are hydrogen. Other particularly preferred compounds are
those where R.sub.3 is methyl and R.sub.4-R.sub.6 are hydrogen or
R.sub.6 is methyl and R.sub.3-R.sub.5 are hydrogen.
Preferred G substituents of the invention include the following:
##STR00033## where R.sub.a represents hydrogen or alkyl where the
alkyl is optionally halogenated; and e is an integer of 1-3.
More preferred G substituents of formula A include those where e is
1, 2, or 3, and R.sub.a is hydrogen, methyl, ethyl, isopropyl, or
cyclopropyl. Particularly preferred G substituents of formula A
include those where e is 1, 2, or 3, and R.sub.a is hydrogen or
methyl.
Another preferred G substituent is the following formula:
##STR00034## where R.sub.a represents hydrogen or alkyl where the
alkyl is optionally halogenated; and e is an integer of 1-3.
More preferred G substituents of formula B include those where e is
1, 2, or 3; and R.sub.a is hydrogen, methyl or ethyl. Particularly
preferred G substituents of formula B include those where e is 1 or
2, and R.sub.a is hydrogen or methyl.
Another preferred G substituent is the following formula:
##STR00035## where Hal represents a halogen, preferably fluoro,
bromo, or chloro; R.sub.a and R.sub.b independently represent
hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.3-C.sub.7cycloalkylC.sub.1-C.sub.6alkyl where the cycloalkyl
group may be substituted with halogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, or mono- or diC.sub.1-C.sub.6 alkylamino;
and e is an integer of 2-3.
Preferred compounds having formula C as the G group include those
where Hal is fluoro and e is 2, 3, or 4.
More preferred G substituents of formula C include those where
R.sub.a is hydrogen, methyl or ethyl; and R.sub.b is hydrogen.
Particularly preferred G substituents of formula C include those
where e is 2; R.sub.a is hydrogen or methyl; and R.sub.b is
hydrogen.
Another preferred G substituent is the following formula:
##STR00036## where Hal represents a halogen, preferably fluoro,
bromo, or chloro; R.sub.a and R.sub.b independently represent
hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.3-C.sub.7cycloalkylC.sub.1-C.sub.6alkyl where the cycloalkyl
group may be substituted with halogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, or mono- or diC.sub.1-C.sub.6 alkylamino;
and e is an integer of 2-3.
Preferred compounds having formula C-1 as the G group include those
where Hal is fluoro and e is 2, 3, or 4.
Another preferred G substituent is the following formula:
##STR00037## where R.sub.a represents hydrogen, alkyl, or C.sub.3-7
cycloalkyl, or a group of the formula: ##STR00038## where p is 1,
2, or 3; D and D' independently represent oxygen, NR.sub.y or
CHR.sub.y, provided that only one of D and D' may be NR.sub.y,
where each R.sub.y is hydrogen or C.sub.1-C.sub.6 alkyl; and
R.sub.z is hydrogen or C.sub.1-C.sub.6 alkyl; and R.sub.b
represents hydrogen, alkyl, or acyl; Y and Y' independently
represent hydrogen or halogen; and e is an integer of 1-3.
More preferred G substituents of formula D are those where Y is
hydrogen or fluorine; and e is 1 or 2. Particularly preferred G
substituents of formula D are those where Y is hydrogen or
fluorine; e is 1 or 2; R.sub.a is hydrogen, C.sub.1-3 alkyl, or
cyclopropyl, and R.sub.b is hydrogen, methyl, or acyl. Other
particularly preferred G substituents of formula D are those where
Y is hydrogen and Y' is fluorine. Still other particularly
preferred G groups of Formula D are those where e is 1 or 2;
R.sub.a is hydrogen, C.sub.1-3 alkyl, cyclopropyl or
cyclopropylmethyl, and R.sub.b is hydrogen, methyl, or acyl.
Another preferred G substituent is the following formula:
##STR00039## where R.sub.a represents hydrogen, alkyl, or C.sub.3-7
cycloalkyl; and R.sub.b represents hydrogen, alkyl, or acyl; or
R.sub.a and R.sub.b independently represent hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.3-7cycloalkylC.sub.1-C.sub.6alkyl; and
Y and Y' independently represent hydrogen or halogen; and e is an
integer of 1-3.
More preferred G substituents of formula D are those where Y is
hydrogen or fluorine; and e is 1 or 2. Particularly preferred G
substituents of formula D are those where Y is hydrogen or
fluorine; e is 1 or 2; R.sub.a is hydrogen, C.sub.1-3 alkyl, or
cyclopropyl, and R.sub.b is hydrogen, methyl, or acyl. Other
particularly preferred G substituents of formula D are those where
Y is hydrogen and Y' is fluorine. Still other particularly
preferred G groups of Formula D are those where e is 1 or 2;
R.sub.a is hydrogen, C.sub.1-3 alkyl, cyclopropyl or
cyclopropylmethyl, and R.sub.b is hydrogen, methyl, or acyl.
Another preferred G substituent is the following formula:
##STR00040## where Z is oxygen, nitrogen, or methylene; and m is 1
or 2.
Particularly preferred G substituents of formula E are those where
Z is oxygen, and m is 1 or 2. Other particularly preferred G
substituents of formula E are those where Z is nitrogen, and m is 1
or 2.
Another preferred G substituent is the following formula:
##STR00041## where Z is oxygen or nitrogen; and m is 1 or 2.
Particularly preferred G substituents of formula F are those where
Z is nitrogen, and m is 1 or 2.
Another preferred G substituent is the following formula:
##STR00042## where Z is oxygen, nitrogen, or methylene; and m is 1
or 2.
Particularly preferred G substituents of formula H are those where
Z is nitrogen, and m is 1 or 2.
Another preferred G substituent is the following formula:
##STR00043## where R.sub.a represents hydrogen, alkyl, or C.sub.3-7
cycloalkyl; R.sub.b represents hydrogen, alkyl, or acyl; Y and Y'
independently represent hydrogen or halogen; and e is an integer of
1-3.
More preferred G substituents of formula J are those where Y and Y'
are independently hydrogen or fluorine; and e is 1 or 2.
Particularly preferred G substituents of formula J are those where
and Y' are independently hydrogen or fluorine; e is 1 or 2; R.sub.a
is hydrogen, C.sub.1-3 alkyl, or cyclopropyl, and R.sub.b is
hydrogen, methyl, or acyl.
Another preferred G substituent is the following formula:
##STR00044## where R.sub.a and R.sub.b independently represent
hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.3-C.sub.7cycloalkylC.sub.1-C.sub.6alkyl where the cycloalkyl
group may be substituted with halogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, or mono- or diC.sub.1-C.sub.6 alkylamino;
and e is an integer of 2-3.
Another preferred G substituent is represented by the following
formula: ##STR00045## where R.sub.h is hydrogen, halogen,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy, or trifluoromethyl; s
is 0, 1, 2 or 3, and the sum of s and m is not less than 1; R.sub.o
is hydroxy, C.sub.1-C.sub.6alkoxy, amino, mono- or
diC.sub.1-C.sub.6alkylamino where each alkyl is independently
optionally substituted with amino, mono- or
diC.sub.1-C.sub.6alkylamino, or R.sub.o is a group of the formula
##STR00046## p is 1, 2, or 3; D and D' independently represent
oxygen, NR.sub.y or CHR.sub.y provided that only one of D and D'
may be NR.sub.y where each R.sub.y is hydrogen or C.sub.1-C.sub.6
alkyl; or and R.sub.z is hydrogen or C.sub.1-C.sub.6 alkyl.
Preferred M groups are those where R.sub.h is hydrogen or halogen,
most preferably fluoro, and R.sub.o is a group of the formula:
##STR00047## where R.sub.14 is hydrogen or C.sub.1-C.sub.6alkyl;
R.sub.15 is hydrogen or C.sub.1-C.sub.6alkyl; R.sub.16 is hydrogen,
ethyl, or methyl; R.sub.17 is C.sub.1-C.sub.6alkyl; and J is a
C.sub.1-C.sub.4 alkylene group, preferably methylene, ethylene, or
propylene.
Particularly preferred groups of Formula M include those where s is
1 and R.sub.o is ethoxy, hydroxy, ethylamino, diethylamino,
morpholinyl, piperazinyl, 4-methylpiperazinyl, ##STR00048##
Other preferred compounds of the invention are those of Formula
N-1. ##STR00049## wherein: n is 1 or 2; X is hydrogen, or alkyl;
R.sub.3, R.sub.4, R.sub.5, and R.sub.6 are the same or different
and are independently selected at each occurrence from hydrogen or
alkyl; and G represents phenyl or pyridyl, each of which is
substituted with a group ##STR00050## and optionally with halogen,
alkyl, alkoxy, hydroxy, amino, or mono- or dialkylamino; where K
and M independently represent a bond or C.sub.1-C.sub.6 alkylene; W
represents --O--, --NH--, --NR.sub.7-- where R.sub.7 represents
hydrogen or alkyl, or C.sub.1-C.sub.3 alkylene; and Z is hydrogen,
hydroxy, cycloalkyl(alkoxy), amino, mono- or di(alkyl.sub.1)amino,
or azacycloalkyl, --O(alkyl.sub.1), --S(O).sub.0-2(alkyl.sub.1),
--C(.dbd.O) (alkyl.sub.1), --OC(.dbd.O)(alkyl.sub.1),
--OC(.dbd.O)H, --C(.dbd.O)O(alkyl.sub.1), --C(.dbd.O)OH,
--C(.dbd.O)NH(alkyl.sub.1), --C(.dbd.O)N(alkyl.sub.1).sub.2,
--C(.dbd.O)NH.sub.2, --NHC(.dbd.O) (alkyl.sub.1), --NHC(.dbd.O)H,
--N(alkyl.sub.1)C(.dbd.O)(alkyl.sub.1),
--NHS(O).sub.0-2(alkyl.sub.1),
--N(alkyl.sub.1)S(O).sub.0-2(alkyl.sub.1),
--S(O).sub.0-2NH(alkyl.sub.1),
--S(O).sub.0-2(alkyl.sub.1)N(alkyl.sub.1), wherein each alkyl.sub.1
is independently straight, branched, or cyclic, may contain one or
two double and/or triple bonds, and is unsubstituted or substituted
with one or more substituents independently selected from hydroxy,
oxo, halogen, amino, cyano, nitro, and alkoxy, or Z is
--N(R.sub.N).sub.2S(O).sub.0-2(R.sub.S) where each R.sub.N is
independently hydrogen or alkyl where the alkyl is straight,
branched, or cyclic, may contain one or two double and/or triple
bonds, and is unsubstituted or substituted with one or more
substituents independently selected from hydroxy, oxo, halogen,
amino, cyano, nitro, and alkoxy, and R.sub.S is hydroxy, alkoxy,
alkyl where the alkyl is optionally substituted with hydroxy,
alkoxy, trifluoromethyl, halogen, amino, mono- or di-alkylamino, or
R.sub.s is heteroaryl unsubstituted or substituted with alkyl,
hydroxy, alkoxy, trifluoromethyl, halogen, amino, or mono- or
dialkylamino; Z is phenyl or phenylalkyl where the phenyl portion
is optionally substituted with alkyl, hydroxy, alkoxy,
trifluoromethyl, halogen, amino, or mono- or di-alkylamino, or Z is
2-, 3-, or 4-pyridyl, 1- or 2-imidazolyl, 1-, 2-, or 3-pyrrolyl,
azeditinyl, norborn-2-yl, or adamantan-2-yl; each of which may be
substituted on a tertiary carbon or a secondary nitrogen with
C.sub.1-C.sub.6alkyl, or Z represents a group of the formula:
##STR00051## where p is 1, 2, or 3; D and D' independently
represent oxygen, NR.sub.y or CHR.sub.y provided that only one of D
and D' may be NR.sub.y where each R.sub.y is hydrogen or alkyl; and
R.sub.z is hydrogen or alkyl, or Z represents a group of the
formula: ##STR00052## where p is 1, 2, or 3; and q is 0, 1, or 2;
or Z represents a group of the formula: ##STR00053## where s is 0,
1, 2 or 3, and the sum of s and m is not less than 1; R.sub.o is
hydroxy, C.sub.1-C.sub.6alkoxy, amino, mono- or dialkylamino where
each alkyl is independently optionally substituted with amino,
mono- or dialkylamino, or R.sub.o is a group of the formula
##STR00054## where p, D, D', and R.sub.z are as defined above.
Preferred compounds of formula N-I include those where X is
hydrogen. Other preferred compounds of formula N-I are those where
X is C.sub.1-C.sub.6 alkyl, most preferably, methyl.
More preferred compounds of N-I are those where K is a bond and W
is oxygen. In other more preferred compounds of formula N-I, K is a
bond and W is a bond or methylene.
Still more preferred compounds of N-I are those where M is C.sub.2
or C.sub.3 alkylene. In other more preferred compounds of formula
N-I, M is C.sub.2 or C.sub.3 alkylene. In these more preferred
compounds of formula N-I, G is phenyl. Alternatively, G is pyridyl
in more preferred compounds of formula N-I.
In preferred compounds of formula N-I, Z is amino, mono- or
di(alkyl)amino, or azacycloalkyl, --O(alkyl),
--S(O).sub.0-2(alkyl), --C(.dbd.O)(alkyl), --OC(.dbd.O)(alkyl),
--OC(.dbd.O)H, --C(.dbd.O)O(alkyl), --C(.dbd.O)OH,
--C(.dbd.O)NH(alkyl), --C(.dbd.O)N(C.sub.1-C.sub.6
alkyl.sub.1).sub.2, --C(.dbd.O)NH.sub.2, --NHC(.dbd.O)(alkyl),
--NHC(.dbd.O)H, --N(alkyl)C(.dbd.O)(alkyl),
--NHS(O).sub.0-2(alkyl), --N(alkyl)S(O).sub.0-2(alkyl),
--S(O).sub.0-2NH(alkyl), --S(O).sub.0-2(alkyl)N(alkyl), or Z is
--N(R.sub.N).sub.2SO.sub.2(R.sub.S) where each R.sub.N is
independently hydrogen or alkyl, and R.sub.S is hydroxy, alkoxy, or
alkyl where the alkyl is optionally substituted with hydroxy,
alkoxy, trifluoromethyl, halogen, amino, or mono- or di-alkylamino,
or R.sub.S is phenyl, imidazolyl, pyridyl, pyrimidinyl, pyrrolyl,
pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, or isothiazolyl, each
of which is optionally substituted with alkyl, hydroxy, alkoxy,
trifluoromethyl, halogen, amino, or mono- or dialkylamino.
Preferred compounds of Formula I above (including all subformulae
such as IIb, IIC etc), exhibit K.sub.i values of less than 100 nM
at the GABA.sub.A receptor as determined by an assay of GABA.sub.A
receptor binding, especially preferred compounds of Formula I-X
exhibit K.sub.i values of less than 10 nM at the GABA.sub.A
receptor as determined by an assay of GABA.sub.A receptor
binding.
Representative compounds of the invention are shown below in Table
1.
TABLE-US-00001 TABLE 1 Compound 1 ##STR00055## Compound 2
##STR00056## Compound 3 ##STR00057## Compound 4 ##STR00058##
Compound 5 ##STR00059## Compound 6 ##STR00060## Compound 7
##STR00061## Compound 8 ##STR00062## Compound 9 ##STR00063##
Compound 10 ##STR00064## Compound 11 ##STR00065## Compound 12
##STR00066## Compound 13 ##STR00067## Compound 14 ##STR00068##
Compound 15 ##STR00069## Compound 47 ##STR00070## Compound 86
##STR00071## Compound 95 ##STR00072## Compound 115 ##STR00073##
Compound 145 ##STR00074## Compound 148 ##STR00075## Compound 149
##STR00076## Compound 179 ##STR00077## Compound 222 ##STR00078##
Compound 226 ##STR00079## Compound 227 ##STR00080## Compound 229
##STR00081## Compound 235 ##STR00082##
The following numbering conventions are used to identify positions
on the ring systems in the compounds of the invention:
##STR00083##
Representative compounds of the present invention, which are
encompassed by Formula I, include, but are not limited to the
compounds in Table I and their pharmaceutically acceptable salts.
Non-toxic pharmaceutically acceptable salts include salts of acids
such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic,
formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric,
tartaric, maleic, hydroiodic, alkanoic such as acetic,
HOOC--(CH.sub.2).sub.n--COOH where n is 0-4, and the like. Those
skilled in the art will recognize a wide variety of non-toxic
pharmaceutically acceptable addition salts.
Representative compounds of the present invention, which are
encompassed by Formula I, include, but are not limited to the
compounds in Table 1 and their pharmaceutically acceptable salts.
The present invention also encompasses the acylated prodrugs of the
compounds of Formula I. Those skilled in the art will recognize
various synthetic methodologies which may be employed to prepare
non-toxic pharmaceutically acceptable addition salts and acylated
prodrugs of the compounds encompassed by Formula I.
This invention relates to fused pyrrolecarboxamide compounds that
bind with high affinity to the benzodiazepine site of GABA.sub.A
receptors, including human GABA.sub.A receptors. This invention
also includes such compounds that bind with high selectivity to the
benzodiazepine site of GABA.sub.A receptors, including human
GABA.sub.A receptors. Without wishing to be bound to any particular
theory, it is believed that the interaction of the compounds of
Formula I with the benzodiazepine site results in the
pharmaceutical utility of these compounds.
The invention further comprises methods of treating patients in
need of such treatment with an amount of a compound of the
invention sufficient to alter the symptoms of a CNS disorder.
Compounds of the inventions that act as agonists at
.alpha..sub.2.beta..sub.3.gamma..sub.2 and
.alpha..sub.3.beta..sub.3.gamma..sub.2 receptor subtypes are useful
in treating anxiety disorders such as panic disorder, obsessive
compulsive disorder and generalized anxiety disorder; stress
disorders including post-traumatic stress, and acute stress
disorders. Compounds of the inventions that act as agonists at
.alpha..sub.2.beta..sub.3.gamma..sub.2 and
.alpha..sub.3.beta..sub.3.gamma..sub.2 receptor subtypes are also
useful in treating depressive or bipolar disorders and in treating
sleep disorders. Compounds of the invention that act as inverse
agonists at the .alpha..sub.5.beta..sub.3.gamma..sub.2 receptor
subtype or .alpha..sub.1.beta..sub.2.gamma..sub.2 and
.alpha..sub.5.beta..sub.3.gamma..sub.2 receptor subtypes are useful
in treating cognitive disorders including those resulting from Down
Syndrome, neurodegenerative diseases such as Alzheimer's disease
and Parkinson's disease, and stroke related dementia. Compounds of
the invention that act as agonists at the
.alpha..sub.1.beta..sub.2.gamma..sub.2 receptor subtype are useful
in treating convulsive disorders such as epilepsy. Compounds that
act as antagonists at the benzodiazepine site are useful in
reversing the effect of benzodiazepine overdose and in treating
drug and alcohol addiction.
The diseases and/or disorders that can also be treated using
compounds and compositions according to the invention include:
Depression, e.g. depression, atypical depression, bipolar disorder,
depressed phase of bipolar disorder.
Anxiety, e.g. general anxiety disorder (GAD), agoraphobia, panic
disorder +/- agoraphobia, social phobia, specific phobia, Post
traumatic stress disorder, obsessive compulsive disorder (OCD),
dysthymia, adjustment disorders with disturbance of mood and
anxiety, separation anxiety disorder, anticipatory anxiety acute
stress disorder, adjustment disorders, cyclothymia.
Sleep disorders, e.g. sleep disorders including primary insomnia,
circadian rhythm sleep disorder, dyssomnia NOS, parasomnias,
including nightmare disorder, sleep terror disorder, sleep
disorders secondary to depression and/or anxiety or other mental
disorders, substance induced sleep disorder.
Cognition Impairment, e.g. cognition impairment, Alzheimer's
disease, Parkinson's disease, mild cognitive impairment (MCI),
age-related cognitive decline (ARCD), stroke, traumatic brain
injury, AIDS associated dementia, and dementia associated with
depression, anxiety or psychosis.
Attention Deficit Disorders, e.g. Attention Deficit Disorder (ADD),
Attention Deficit and Hyperactivity Disorder (ADHD).
The invention also provides pharmaceutical compositions comprising
compounds of the invention, including packaged pharmaceutical
compositions for treating disorders responsive to GABA.sub.A
receptor modulation, e.g., treatment of anxiety, depression, sleep
disorders or cognitive impairment by GABA.sub.A receptor
modulation. The packaged pharmaceutical compositions include a
container holding a therapeutically effective amount of at least
one GABA.sub.A receptor modulator as described supra and
instructions (e.g., labeling) indicating the contained GABA.sub.A
receptor ligand is to be used for treating a disorder responsive to
GABA.sub.A receptor modulation in the patient.
In a separate aspect, the invention provides a method of
potentiating the actions of other CNS active compounds, which
comprises administering an effective amount of a compound of the
invention in combination with another CNS active compound. Such CNS
active compounds include, but are not limited to the following: for
anxiety, serotonin receptor (e.g. 5-HT.sub.1A) agonists and
antagonists; for anxiety and depression, neurokinin receptor
antagonists or corticotropin releasing factor receptor (CRF.sub.1)
antagonists; for sleep disorders, melatonin receptor agonists; and
for neurodegenerative disorders, such as Alzheimer's dementia,
nicotinic agonists, muscarinic agents, acetylcholinesterase
inhibitors and dopamine receptor agonists. Particularly the
invention provides a method of potentiating the antidepressant
activity of selective serotonin reuptake inhibitors (SSRIs) by
administering an effective amount of a GABA agonist compound of the
invention in combination with an SSRI.
Combination administration can be carried out in a fashion
analogous to that disclosed in Da-Rocha, et al., J.
Psychopharmacology (1997) 11(3) 211-218; Smith, et al., Am. J.
Psychiatry (1998) 155(10) 1339-45; or Le, et al., Alcohol and
Alcoholism (1996) 31 Suppl. 127-132. Also see, the discussion of
the use of the GABA.sub.A receptor ligand
3-(5-methylisoxazol-3-yl)-6-(1-methyl-1,2,3-triazol-4-yl)
methyloxy-1,2,4-triazolo [3,4-a]phthalzine in combination with
nicotinic agonists, muscarinic agonists, and acetylcholinesterase
inhibitors, in PCT International publications Nos. WO 99/47142, WO
99/47171, and WO 99/47131, respectively. Also see in this regard
PCT International publication No. WO 99/37303 for its discussion of
the use of a class of GABA.sub.A receptor ligands,
1,2,4-triazolo[4,3-b]pyridazines, in combination with SSRIs.
The present invention also pertains to methods of inhibiting the
binding of benzodiazepine compounds, such as Ro15-1788, to the
GABA.sub.A receptors which methods involve contacting a compound of
the invention with cells expressing GABA.sub.A receptors, wherein
the compound is present at a concentration sufficient to inhibit
benzodiazepine binding to GABA.sub.A receptors in vitro. This
method includes inhibiting the binding of benzodiazepine compounds
to GABA.sub.A receptors in vivo, e.g., in a patient given an amount
of a compound of Formula I that would be sufficient to inhibit the
binding of benzodiazepine compounds to GABA.sub.A receptors in
vitro. In one embodiment, such methods are useful in treating
benzodiazepine drug overdose. The amount of a compound that would
be sufficient to inhibit the binding of a benzodiazepine compound
to the GABA.sub.A receptor may be readily determined via an
GABA.sub.A receptor binding assay, such as the assay described in
Example 8. The GABA.sub.A receptors used to determine in vitro
binding may be obtained from a variety of sources, for example from
preparations of rat cortex or from cells expressing cloned human
GABA.sub.A receptors.
The present invention also pertains to methods for altering the
signal-transducing activity, particulary the chloride ion
conductanc of GABA.sub.A receptors, said method comprising exposing
cells expressing such receptors to an effective amount of a
compound of the invention. This method includes altering the
signal-transducing activity of GABA.sub.A receptors in vivo, e.g.,
in a patient given an amount of a compound of Formula I that would
be sufficient to alter the signal-transducing activity of
GABA.sub.A receptors in vitro. The amount of a compound that would
be sufficient to alter the signal-transducing activity of
GABA.sub.A receptors may be determined via a GABA.sub.A receptor
signal transduction assay, such as the assay described in Example
9.
The GABA.sub.A receptor ligands provided by this invention and
labeled derivatives thereof are also useful as standards and
reagents in determining the ability of a potential pharmaceutical
to bind to the GABA.sub.A receptor.
Labeled derivatives the GABA.sub.A receptor ligands provided by
this invention are also useful as radiotracers for positron
emission tomography (PET) imaging or for single photon emission
computerized tomography (SPECT).
Definitions
If the compounds of the present invention have asymmetric centers,
then this invention includes all of the optical isomers and
mixtures thereof.
In addition, compounds with carbon-carbon double bonds may occur in
cis, trans, Z- and E- forms, with all isomeric forms of the
compounds being included in the present invention.
A dashed line ( - - - ) in a Formula indicates an optional bond.
Thus the Formula ##STR00084## represents either ##STR00085##
When any variable (e.g., C.sub.1-C.sub.6 alkyl, alkyl.sub.1,
R.sub.3, R.sub.4, R.sub.5, R.sub.6, X, T, G, W, Z, k, or m) occurs
more than one time in Formula I, its definition on each occurrence
is independent of its definition at every other occurrence.
By "alkyl" or "lower alkyl" in the present invention is meant
straight or branched chain alkyl groups having 1-6 carbon atoms,
such as, for example, methyl, ethyl, propyl, isopropyl, n-butyl,
sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl,
hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl.
By "alkoxy" or "lower alkoxy" in the present invention is meant
straight or branched chain alkyl group having 1-6 carbon atoms,
attached to the parent molecular moiety through an oxygen atom.
Examples of alkoxy groups include, for example, methoxy, ethoxy,
propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy,
2-pentyl, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, and
3-methylpentoxy.
The term "alkenyl" is intended to include either straight or
branched hydrocarbon chains containing at least one carbon-carbon
double bond which may occur in any stable point along the chain.
Examples of alkenyl groups include ethenyl and propenyl.
The term "alkynyl" is intended to include either a straight or
branched hydrocarbon chain containing at least one carbon-carbon
triple bond which may occur in any stable point along the chain,
such as ethynyl and propynyl.
By "diC.sub.1-C.sub.6alkylamino" is meant an amino group carrying
two C.sub.1-C.sub.6alkyl groups that are the same or different.
By "benzoxazinyl" as used herein is meant a moiety of the formula:
##STR00086##
A benzoxazin-6-yl group is depicted.
By "halogen" in the present invention is meant fluorine, bromine,
chlorine, and iodine.
By "2-hydroxyethoxy" is meant a group of the formula:
--OCH.sub.2CH.sub.2OH.
The term "aryl" refers to an aromatic hydrocarbon ring system
containing at least one aromatic ring. The aromatic ring may
optionally be fused or otherwise attached to other aromatic
hydrocarbon rings or non-aromatic hydrocarbon rings. Examples of
aryl groups include, for example, phenyl, naphthyl,
1,2,3,4-tetrahydronaphthalene and biphenyl. Preferred examples of
aryl groups include phenyl and naphthyl. The aryl groups of the
invention are unsubstituted or may be substituted as provided
herein. Examples of suitable substituents include hydroxy, halogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, cyano, nitro, amino,
mono- or dialkyl(C.sub.1-C.sub.6)amino, carboxamide, and N-mono- or
N,N-disubstituted carboxamide.
The term "heteroaryl" refers to an aromatic ring system containing
at least one heteroatom selected from nitrogen, oxygen, and sulfur.
The heteroaryl ring may be fused or otherwise attached to one or
more heteroaryl rings, aromatic or non-aromatic hydrocarbon rings
or heterocycloalkyl rings. Examples of heteroaryl groups include,
for example, pyridine, furan, thiophene,
5,6,7,8-tetrahydroisoquinoline and pyrimidine. Preferred examples
of heteroaryl groups include thienyl, benzothienyl, pyridyl,
quinolyl, pyrazinyl, pyrimidinyl, imidazolyl, benzimidazolyl,
furanyl, benzofuranyl, thiazolyl, thiadiazolyl, benzothiazolyl,
imidazo[1,2-a]pyridinyl, isoxazolyl, oxadiazolyl, isothiazolyl,
benzisothiazolyl, triazolyl, tetrazolyl, pyrrolyl, indolyl,
pyrazolyl, and benzopyrazolyl. These heteroaryl groups can be
unsubstituted or may be substituted as provided herein. Examples of
suitable substituents include hydroxy, halogen, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 alkoxy, cyano, nitro, amino, mono- or
dialkyl(C.sub.1-C.sub.6)amino, carboxamide, and N-mono- or
N,N-disubstituted carboxamide.
By a 2-, 3-, or 4-pyridyl, 1- or 2-imidazolyl, 1-, 2-, or
3-pyrrolyl, or adamantane-2-yl group that is substituted on a
tertiary carbon or a secondary nitrogen with C.sub.1-C.sub.6 alkyl
is meant any such group in which a hydrogen atom is replaced with
an appropriate alkyl group. By way of example, such groups include
the following: ##STR00087##
By "heterocycloalkyl" is meant a non-aromatic ring system
comprising one or two rings of 4-, 5-, 6-, or 7-atoms per ring
wherein at least one ring contains at least one and up to 4
heteroatoms selected from nitrogen, oxygen, or sulfur. Such
heterocycloalkyl groups include, for example, tetrahydropyridyl,
morpholinyl, thiomorpholinyl, pyrrolidinyl, piperazinyl, and
tetrahydrofuryl. The heterocycloalkyl group can be attached to the
parent molecular moiety through the heteroatom or through a carbon
atom. These groups may be substituted with from one to four groups
independently selected from alkyl, alkoxy, halogen, hydroxy, amino
and mono- or dialkylamino groups. Preferred substituents are
hydroxy, methoxy, ethoxy, chloro, fluoro, bromo, methyl and ethyl.
More preferred heterocycloalkyl groups are those that are
independently substituted with two of hydroxy, methoxy, ethoxy,
chloro, fluoro, bromo, methyl or ethyl. Particularly preferred
heterocycloalkyl groups are those that are substituted with one of
hydroxy, methoxy, ethoxy, chloro, fluoro, bromo, methyl or
ethyl.
By "N-alkylpiperazyl" in the invention is meant radicals of the
formula: ##STR00088## where R is a straight or branched chain lower
alkyl as defined above.
By "acyclic moiety having 3-7 carbon atoms" is meant a cytobutyl,
cyclopentyl, cyclohexyl or cycloheptyl. Each of these groups may be
substituted with alkyl, alkoxy, hydroxy, halogen, amino or mono- or
dialkylamino. Preferred substituents are alkyl and alkoxy.
Particularly preferred are alkyl with methyl and ethyl being most
preferred.
Non-toxic pharmaceutically acceptable salts include, but are not
limited to salts of inorganic acids such as hydrochloric, sulfuric,
phosphoric, diphosphoric, hydrobromic, and nitric or salts of
organic acids such as formic, citric, malic, maleic, fumaric,
tartaric, succinic, acetic, lactic, methanesulfonic,
p-toluenesulfonic, 2-hydroxyethylsulfonic, salicylic and stearic.
Similarly, pharmaceutically acceptable cations include, but are not
limited to sodium, potassium, calcium, aluminum, lithium and
ammonium. Those skilled in the art will recognize a wide variety of
non-toxic pharmaceutically acceptable addition salts. The present
invention also encompasses prodrugs of the compounds of Formula
I.
The present invention also encompasses the acylated prodrugs of the
compounds of Formula I. Those skilled in the art will recognize
various synthetic methodologies, which may be employed to prepare
non-toxic pharmaceutically acceptable addition salts and acylated
prodrugs of the compounds encompassed by Formula I.
Pharmaceutical Compositions
Those skilled in the art will recognize various synthetic
methodologies that may be employed to prepare non-toxic
pharmaceutically acceptable prodrugs of the compounds encompassed
by Formula I. Those skilled in the art will recognize a wide
variety of non-toxic pharmaceutically acceptable solvents that may
be used to prepare solvates of the compounds of the invention, such
as water, ethanol, mineral oil, vegetable oil, and
dimethylsulfoxide.
The compounds of general Formula I may be administered orally,
topically, parenterally, by inhalation or spray or rectally in
dosage unit formulations containing conventional non-toxic
pharmaceutically acceptable carriers, adjuvants and vehicles. Oral
administration in the form of a pill, capsule, elixir, syrup,
lozenge, troche, or the like is particularly preferred. The term
parenteral as used herein includes subcutaneous injections,
intradermal, intravascular (e.g., intravenous), intramuscular,
spinal, intrathecal injection or like injection or infusion
techniques. In addition, there is provided a pharmaceutical
formulation comprising a compound of general Formula I and a
pharmaceutically acceptable carrier. One or more compounds of
general Formula I may be present in association with one or more
non-toxic pharmaceutically acceptable carriers and/or diluents
and/or adjuvants and if desired other active ingredients. The
pharmaceutical compositions containing compounds of general Formula
I may be in a form suitable for oral use, for example, as tablets,
troches, lozenges, aqueous or oily suspensions, dispersible powders
or granules, emulsion, hard or soft capsules, or syrups or
elixirs.
Compositions intended for oral use may be prepared according to any
method known to the art for the manufacture of pharmaceutical
compositions and such compositions may contain one or more agents
selected from the group consisting of sweetening agents, flavoring
agents, coloring agents and preserving agents in order to provide
pharmaceutically elegant and palatable preparations. Tablets
contain the active ingredient in admixture with non-toxic
pharmaceutically acceptable excipients that are suitable for the
manufacture of tablets. These excipients may be for example, inert
diluents, such as calcium carbonate, sodium carbonate, lactose,
calcium phosphate or sodium phosphate; granulating and
disintegrating agents, for example, corn starch, or alginic acid;
binding agents, for example starch, gelatin or acacia, and
lubricating agents, for example magnesium stearate, stearic acid or
talc. The tablets may be uncoated or they may be coated by known
techniques to delay disintegration and absorption in the
gastrointestinal tract and thereby provide a sustained action over
a longer period. For example, a time delay material such as
glyceryl monosterate or glyceryl distearate may be employed.
Formulations for oral use may also be presented as hard gelatin
capsules wherein the active ingredient is mixed with an inert solid
diluent, for example, calcium carbonate, calcium phosphate or
kaolin, or as soft gelatin capsules wherein the active ingredient
is mixed with water or an oil medium, for example peanut oil,
liquid paraffin or olive oil.
Aqueous suspensions contain the active materials in admixture with
excipients suitable for the manufacture of aqueous suspensions.
Such excipients are suspending agents, for example sodium
carboxymethylcellulose, methylcellulose,
hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone,
gum tragacanth and gum acacia; dispersing or wetting agents may be
a naturally-occurring phosphatide, for example, lecithin, or
condensation products of an alkylene oxide with fatty acids, for
example polyoxyethylene stearate, or condensation products of
ethylene oxide with long chain aliphatic alcohols, for example
heptadecaethyleneoxycetanol, or condensation products of ethylene
oxide with partial esters derived from fatty acids and a hexitol
such as polyoxyethylene sorbitol monooleate, or condensation
products of ethylene oxide with partial esters derived from fatty
acids and hexitol anhydrides, for example polyethylene sorbitan
monooleate. The aqueous suspensions may also contain one or more
preservatives, for example ethyl, or n-propyl p-hydroxybenzoate,
one or more coloring agents, one or more flavoring agents, and one
or more sweetening agents, such as sucrose or saccharin.
Oily suspensions may be formulated by suspending the active
ingredients in a vegetable oil, for example arachis oil, olive oil,
sesame oil or coconut oil, or in a mineral oil such as liquid
paraffin. The oily suspensions may contain a thickening agent, for
example beeswax, hard paraffin or cetyl alcohol. Sweetening agents
such as those set forth above, and flavoring agents may be added to
provide palatable oral preparations. These compositions may be
preserved by the addition of an anti-oxidant such as ascorbic
acid.
Dispersible powders and granules suitable for preparation of an
aqueous suspension by the addition of water provide the active
ingredient in admixture with a dispersing or wetting agent,
suspending agent and one or more preservatives. Suitable dispersing
or wetting agents and suspending agents are exemplified by those
already mentioned above. Additional excipients, for example
sweetening, flavoring and coloring agents, may also be present.
Pharmaceutical compositions of the invention may also be in the
form of oil-in-water emulsions. The oily phase may be a vegetable
oil, for example olive oil or arachis oil, or a mineral oil, for
example liquid paraffin or mixtures of these. Suitable emulsifying
agents may be naturally-occurring gums, for example gum acacia or
gum tragacanth, naturally-occurring phosphatides, for example soy
bean, lecithin, and esters or partial esters derived from fatty
acids and hexitol, anhydrides, for example sorbitan monooleate, and
condensation products of the said partial esters with ethylene
oxide, for example polyoxyethylene sorbitan monoleate. The
emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, for
example glycerol, propylene glycol, sorbitol or sucrose. Such
formulations may also contain a demulcent, a preservative and
flavoring and coloring agents. The pharmaceutical compositions may
be in the form of a sterile injectable aqueous or oleaginous
suspension. This suspension may be formulated according to the
known art using those suitable dispersing or wetting agents and
suspending agents which have been mentioned above. The sterile
injectable preparation may also be sterile injectable solution or
suspension in a non-toxic parentally acceptable diluent or solvent,
for example as a solution in 1,3-butanediol. Among the acceptable
vehicles and solvents that may be employed are water, Ringer's
solution and isotonic sodium chloride solution. In addition,
sterile, fixed oils are conventionally employed as a solvent or
suspending medium. For this purpose any bland fixed oil may be
employed including synthetic mono- or diglycerides. In addition,
fatty acids such as oleic acid find use in the preparation of
injectables.
The compounds of general Formula I may also be administered in the
form of suppositories, e.g., for rectal administration of the drug.
These compositions can be prepared by mixing the drug with a
suitable non-irritating excipient that is solid at ordinary
temperatures but liquid at the rectal temperature and will
therefore melt in the rectum to release the drug. Such materials
are cocoa butter and polyethylene glycols.
Compounds of general Formula I may be administered parenterally in
a sterile medium. The drug, depending on the vehicle and
concentration used, can either be suspended or dissolved in the
vehicle. Advantageously, adjuvants such as local anesthetics,
preservatives and buffering agents can be dissolved in the
vehicle.
For administration to non-human animals, the composition may also
be added to the animal feed or drinking water. It will be
convenient to formulate these animal feed and drinking water
compositions so that the animal takes in an appropriate quantity of
the composition along with its diet. It will also be convenient to
present the composition as a premix for addition to the feed or
drinking water.
Dosage levels of the order of from about 0.1 mg to about 140 mg per
kilogram of body weight per day are useful in the treatment of the
above-indicated conditions (about 0.5 mg to about 7 g per patient
per day). The amount of active ingredient that may be combined with
the carrier materials to produce a single dosage form will vary
depending upon the host treated and the particular mode of
administration. Dosage unit forms will generally contain between
from about 1 mg to about 500 mg of an active ingredient.
Frequency of dosage may also vary depending on the compound used
and the particular disease treated. However, for treatment of most
disorders, a dosage regimen of 4 times daily or less is preferred.
For the treatment of anxiety, depression, or cognitive impairment a
dosage regimen of 1 or 2 times daily is particularly preferred. For
the treatment of sleep disorders a single dose that rapidly reaches
effective concentrations is desirable.
It will be understood, however, that the specific dose level for
any particular patient will depend upon a variety of factors
including the activity of the specific compound employed, the age,
body weight, general health, sex, diet, time of administration,
route of administration, and rate of excretion, drug combination
and the severity of the particular disease undergoing therapy.
Preferred compounds of the invention will have desirable
pharmacological properties. Such properties include, but are not
limited to oral bioavailability, low toxicity, low serum protein
binding and desirable in vitro and in vivo half-lifes. Penetration
of the blood brain barrier for compounds used to treat CNS
disorders is necessary, while low brain levels of compounds used to
treat peripheral disorders are often preferred.
Assays may be used to predict these desirable pharmacological
properties. Assays used to predict bioavailability include
transport across human intestinal cell monolayers, including Caco-2
cell monolayers. Toxicity to cultured hepatocyctes may be used to
predict compound toxicity. Penetration of the blood brain barrier
of a compound in humans may be predicted from the brain levels of
the compound in laboratory animals given the compound
intravenously.
Serum protein binding may be predicted from albumin binding assays.
Such assays are described in a review by Oravcova, et al. (Journal
of Chromatography B (1996) volume 677, pages 1-27).
Compound half-life is inversely proportional to the frequency of
dosage of a compound. In vitro half-lifes of compounds may be
predicted from assays of microsomal half-life as described by Kuhnz
and Gieschen (Drug Metabolism and Disposition, (1998) volume 26,
pages 1120-1127).
Preparation of Compounds
A general illustration of the preparation of compounds of Formula I
in the present invention is given in Scheme I. ##STR00089##
where:
Ar is ##STR00090## where Q, W, k, m, n, Z, R.sub.3, R.sub.4,
R.sub.5, and R.sub.6 are as defined above.
Those having skill in the art will recognize that the starting
materials may be varied and additional steps employed to produce
compounds encompassed by the present invention, as demonstrated by
the following examples.
In some cases protection of reactive functionalities may be
necessary to achieve some of the above transformations. In general
the need for such protecting groups will be apparent to those
skilled in the art of organic synthesis as well as the conditions
necessary to attach and remove such groups. Representative examples
of the preparation of various protected aniline derivatives are
shown in Schemes II (1), (2) and (3). ##STR00091##
Compounds of Formula I where G is a group of, for example, formulas
C, C-1, D, D-1, K or M can be made using the above outlined methods
and, e.g., additional ester and amide coupling reactions. It may
also be necessary to protect the indole ring nitrogen during the
preparation of the compounds of the invention.
For example, compounds where R.sub.0 is a dialkylamino group can be
prepared from a 2-(4-nitrophenoxy)ethan-1-ol made as described
above and oxidation of the hydroxy group, and subsequent formation
of an acid chloride or active ester. The active ester or acid
chloride may then be coupled to an appropriate amine and the
resulting nitrophenyl compound used as shown in the above schemes.
##STR00092## ##STR00093##
Those skilled in the art will recognize that in certain instances
it will be necessary to utilize different solvents or reagents to
achieve some of the above transformations. Unless otherwise
specified all reagents and solvent are of standard commercial grade
and are used without further purification.
The invention is illustrated further by the following examples,
which are not to be construed as limiting the invention in scope or
spirit to the specific procedures described in them. Those having
skill in the art will recognize that the starting materials may be
varied and additional steps employed to produce compounds
encompassed by the present inventions, as demonstrated by the
following examples. In some cases, protection of certain reactive
functionalities may be necessary to achieve some of the above
transformations. In general, such need for protecting groups, as
well as the conditions necessary to attach and remove such groups,
will be apparent to those skilled in the art of organic
synthesis.
EXAMPLES
Example 1
Preparation of Starting Materials and Intermediates
The starting materials and various intermediates may be obtained
from commercial sources, prepared from commercially available
organic compounds, or prepared using well known synthetic
methods.
Representative examples of methods for preparing intermediates of
the invention are set forth below.
1. 4-oxo-4,5,6,7-tetrahydrobenzofuran-3-carboxylic acid
##STR00094##
4-Oxo-4,5,6,7-tetrahydrobenzofuran-3-carboxylic acid is prepared
according to the following procedure. Potassium hydroxide (345 g,
6.15 mol) is dissolved in methyl alcohol (1.2 L) then cooled in an
ice water bath. A solution of cyclohexanedione (714 g, 6.15 mol) in
methyl alcohol (1.2 L), dissolved using gentle heat, is added
dropwise to the cold, stirred KOH solution over 2 h. A solution of
ethyl bromopyruvate (1200 g, 6.15 mol) in methyl alcohol (1.5 L) is
then added dropwise over 3 h. The reaction mixture is allowed to
reach ambient temperature and stirred an additional 14.5 h. While
cooling the reaction mixture via a water bath, a solution of sodium
hydroxide (492 g, 12.4 mol) in water (984 mL) is added dropwise
over 2.5 h. After stirring at ambient temperature for 15.5 h, the
reaction mixture is cooled in an ice water bath, 500 g of ice
added, and the resulting mixture is then acidified with
concentrated hydrochloric acid (ca 1 L) to pH 1. The reaction
mixture is concentrated in vacuo, 1 L of ice is added, and the
precipitate filtered, washed with ice water (3.times.200 mL), and
then dried in a vacuum oven at 75.degree. C. to afford
4-oxo-4,5,6,7-tetrahydrobenzofuran-3-carboxylic acid (560 g). m.p.
137-138.degree. C.
2. 4-oxo-4,5,6,7-tetrahydroindole-3-carboxylate
##STR00095##
To a stirred mixture of
4-oxo-4,5,6,7-tetrahydrobenzofuran-3-carboxylic acid (640 g, 3.55
mol), potassium carbonate (1.7 kg, 10.65 mol) and cesium carbonate
(100 g, 0.32 mol) in N,N-dimethylformamide (9.0 L) is added
iodoethane (1250 g, 8.01 mol). The mixture is heated at 60.degree.
C. for 2 h. After cooling to ambient temperature, the mixture is
filtered, the solid is rinsed with ethyl acetate, and the filtrate
concentrated in vacuo. Water (2 L) is added then extracted with
ethyl acetate (2.times.2 L); the combined organic extracts are
washed with brine, dried over magnesium sulfate, filtered, and
concentrated in vacuo to give ethyl
4-oxo-4,5,6,7-tetrahydrobenzofuran-3-carboxylic acid (642 g). A
mixture of this ester (640 g, 3.07 mol) and ammonium acetate (426
g, 5.53 mol) in N,N-dimethylformamide (320 mL) is heated to
100.degree. C. for 2 h. The reaction mixture is concentrated in
vacuo, ice water (2.5 L) is added, and extracted with
dichloromethane (2.times.3 L); the combined organic extracts are
washed with brine, dried over magnesium sulfate, filtered, and
concentrated in vacuo to give ethyl
4-oxo-4,5,6,7-tetrahydroindole-3-carboxylate (357 g). A mixture of
this ester (170 g, 0.82 mol) in ethyl alcohol (250 mL) and a
solution of sodium hydroxide (165 g, 4.1 mol) in water (1 L) is
heated at reflux for 1 h, then cooled in an ice water bath.
Concentrated hydrochloric acid (350 mL) is added dropwise, the
precipitate collected by filtration, rinsed with ice water
(3.times.), and dried in a vacuum oven at 75.degree. C. to afford
125 g of 4-oxo-4,5,6,7-tetrahydroindole-3-carboxylate. m.p. 269-270
C.
3. 4-[N-trifluoroacetyl-(methylaminomethyl)aniline
##STR00096##
A solution of p-nitrobenzylbromide (5.40 g, 25 mmol) in
acetonitrile (60 ml) is added dropwise to a stirred solution of
aqueous methylamine (65 mL, 40 wt. %, 0.75 mol) in acetonitrile (50
mL) at 0.degree.. After stirring an additional 15 minutes, the
solution is poured into brine and extracted 2.times. with
dichloromethane. The combined organic layers are washed with brine,
dried over sodium sulfate, filtered, and concentrated in vacuo to
give 4-(methylaminomethyl)nitrobenzene (4.04 g).
A solution of trifluoroacetic anhydride (4.46 mL, 31.6 mmol) in
dichloromethane (10 mL) is added dropwise to a stirred solution of
4-(methylaminomethyl)nitrobenzene (4.04 g, 24.3 mmol) and pyridine
(2.16 mL, 26.7 mmol) in dichloromethane (25 mL) at 0.degree.. After
stirring an additional 30 minutes, the solution is poured into
aqueous 3.6N hydrochloric acid and extracted with dichloromethane.
The organic layer is washed with brine, dried over sodium sulfate,
filtered, and concentrated in vacuo to give
4-[N-trifluoroacetyl-(methylaminomethyl)]nitrobenzene (6.55 g).
Crude 4-[N-trifluoroacetyl-(methylaminomethyl)]nitrobenzene (6.55
g) is dissolved in ethyl alcohol (75 mL), added to 10% Pd/C (655
mg) in a Parr bottle and shaken under Hydrogen (50 PSI) for 4
hours. The mixture is filtered through Celite and concentrated in
vacuo to give 4-[N-trifluoroacetyl-(methylaminomethyl)aniline (5.75
g).
The 3-aminoalkylanilines are prepared in a similar fashion
according to the procedure generally set forth in part (1) of
Scheme II above.
4. 4-amino-(N-trifluoroacetyl-2-methylaminoethoxy)benzene
##STR00097##
A mixture of p-nitrophenol (1.39 g, 10 mmol),
2-chloroethoxytrimethylsilane (3.2 ml, 20 mmol), potassium
carbonate (4.15 g, 30 mmol), cesium carbonate (163 mg, 0.5 mmol),
and sodium iodide (149 mg, 1 mmol) in N,N-dimethylformamide (10 ml)
is heated at 75.degree. for 19.5 hours. After cooling to ambient
temperature, the mixture is diluted with ethyl acetate and
filtered. The filtrate is washed with saturated aqueous sodium
bicarbonate, then washed 2.times. with water, dried over magnesium
sulfate, filtered, concentrated in vacuo, and purified on Silica
gel (1:1 ethyl acetate/hexanes) to give
4-nitro-(2-Hydroxyethoxy)benzene (1.25 g).
4-Nitro-(2-Hydroxyethoxy)benzene (1.13 g, 6.2 mmol) in thionyl
chloride (10 mL) is heated at reflux for 3 hours then concentrated
in vacuo. After cooling the residue in an ice water bath, saturated
aqueous sodium bicarbonate is added and the precipitate collected,
rinsed with water, and dried to give
4-nitro-(2-chloroethoxy)benzene (909 mg).
A mixture of 4-nitro-(2-chloroethoxy)benzene (781 mg, 3.9 mmol) and
aqueous methylamine (15 mL, 40 wt. %) in isopropyl alcohol (15 mL)
is heated in a sealed tube at 100.degree. for 4 hours. After
cooling in an ice water bath, the mixture is poured into brine and
extracted 2.times. with dichloromethane, dried over sodium sulfate,
filtered, and concentrated in vacuo to give
4-nitro-(2-methylaminoethoxy)benzene (697 mg).
To a solution of 4-nitro-(2-methylaminoethoxy)benzene (766 mg, 3.9
mmol) and pyridine (0.35 mL, 4.29 mmol) in dichloromethane (5 mL)
at 0.degree. C. is added dropwise trifluoroacetic anhydride (0.72
mL, 5.08 mmol). After stirring at 0.degree. C. for 3.5 hours, the
mixture is poured into aqueous 1.2 N hydrochloric acid and
extracted with dichloromethane. The organic layer is washed with
saturated aqueous sodium bicarbonate then brine, dried over sodium
sulfate, filtered, and concentrated in vacuo to give
4-nitro-(N-trifluoroacetyl-2-methylaminoethoxy)benzene (1.06 g).
Treatment of this nitro compound with 10% Palladium on carbon in
ethyl alcohol (18 mL) in a Parr bottle under Hydrogen (55 PSI) for
2.25 hours affords
4-amino-(N-trifluoroacetyl-2-methylaminoethoxy)benzene (709
mg).
Example 2
##STR00098##
To a stirred solution of
4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (100 mg, 0.6
mmol) and triethylamine (0.15 mL, 1.1 mmol) in
N,N-dimethylformamide (5 mL) at 0.degree. C. is added ethyl
chloroformate (0.1 mL, 1.1 mmol). After stirring an additional 1
hour, 3-(N-trifluoroacetyl-(methylaminomethyl)aniline (0.3 g, 1.3
mmol) is added. The reaction mixture is stirred for 4 hours, then
poured into saturated aqueous ammonium chloride and extracted
2.times. with ethyl acetate. The combined organic layers are washed
sequentially with brine, aqueous 2N hydrochloric acid, then brine,
dried over sodium sulfate, filtered, and concentrated in vacuo. To
the residue is added 15% aqueous potassium bicarbonate (5 mL) and
methyl alcohol (3 mL), then heated at reflux for 3 hours. After
cooling, the reaction mixture is extracted with ethyl acetate, the
organic layer dried over sodium sulfate, filtered, and concentrated
in vacuo to give
N-[3-(methylaminomethyl)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carb-
oxamide; (Compound 1) m.p. 130-132.degree. C.
Example 3
The following compounds are prepared essentially according to the
procedures described in Schemes I-IV and further illustrated in
Examples 1-2: (a)
N-[3-(Methylaminomethyl)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indo-
le-3-carboxamide (Compound 1); mp 130-132.degree. C. (b)
N-[4-(Hydroxyethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxam-
ide (Compound 16); mp 245-247.degree. C. (c)
N-[4-(Methoxyethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxam-
ide (Compound 2). (d)
N-[-4-(3-Methylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-c-
arboxamide (Compound 17); mp 233-236.degree. C. (e)
N-[4-(Methoxymethyl)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxam-
ide (Compound 18); mp 164-165.degree. C. (f)
N-[4-(Aminomethyl)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamid-
e (Compound 6); mp >200.degree. C. (d). (g)
N-[4-(Methylaminomethyl)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carb-
oxamide (Compound 19); mp 217-219.degree. C. (h)
N-[2-Fluoro-4-(methylaminomethyl)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indo-
le-3-carboxamide (Compound 3); mp 186-188.degree. C. (i)
N-{4-[N-acetyl-(methylaminomethyl)phenyl]}-4-oxo-4,5,6,7-tetrahydro-1H-in-
dole-3-carboxamide (Compound 20); mp 204-206.degree. C. (j)
N-[4-(Ethylaminomethyl)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carbo-
xamide (Compound 21); mp 194-195.degree. C. (k)
N-[4-(Isopropylaminomethyl)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-c-
arboxamide (Compound 22); mp 164-166.degree. C. (l)
N-[4-(Cyclopropylaminomethyl)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-
-carboxamide (Compound 5); mp 171-173.degree. C. (m)
N-[4-(Dimethylaminomethyl)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-ca-
rboxamide (Compound 23); mp 216-218.degree. C. (n)
N-[4-(2-Aminoethyl)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-ndole-3-carboxamid-
e (Compound 24); mp 85-90.degree. C. (o)
N-[4-(2-Methylaminoethyl)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-car-
boxamide (Compound 4); mp 197-200.degree. C. (p)
N-[4-(Methoxymethyl)phenyl]-4-oxo-5,5-dimethyl-4,5,6,7-tetrahydro-1H-indo-
le-3-carboxamide (Compound 25). (q)
N-[4-(Methylaminomethyl)phenyl-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]p-
yrrole-3-carboxamide (Compound 7); mp 173-175.degree. C. (r)
N-{4-[N-acetyl-(methylaminomethyl)phenyl]}-4-oxo-6-methyl-4,5,6,7-tetrahy-
dro-1H-indole-3-carboxamide (Compound 26); mp 159-161.degree. C.
(s)
N-[4-(Methylaminomethyl)phenyl]-4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indo-
le-3-carboxamide (Compound 27); mp 217-219.degree. C. (t)
N-[4-(Hydroxymethyl)phenyl]-4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-
-carboxamide (Compound 28); mp 260-262.degree. C. (u)
N-[4-(2-Hydroxyethoxy)phenyl]-4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-
-3-carboxamide (Compound 9); mp 245-247.degree. C. (v)
N-[3-(Methylaminomethyl)phenyl]-4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indo-
le-3-carboxamide (Compound 29); mp 172-174.degree. C. (w)
N-[4-(2-Hydroxyethoxy)phenyl]-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-in-
dole-3-carboxamide (Compound 30); mp 268-270.degree. C. (x)
N-[3-(Hydroxymethyl)phenyl]-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indo-
le-3-carboxamide (Compound 8); mp 233-235.degree. C. (y)
N-[4-(Hydroxymethyl)phenyl]-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indo-
le-3-carboxamide (Compound 31); mp 245-247.degree. C. (z)
N-[4-(Methylaminomethyl)phenyl]-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H--
indole-3-carboxamide (Compound 32); mp 230-232.degree. C. (aa)
N-(1,3-Benzodioxol-5-yl)-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide
(Compound 10); mp 248-249.degree. C. (bb)
N-(2,3-Dihydro-1,4-benzodioxin-6-yl)-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-
-carboxamide (Compound 11); mp 254-256.degree. C. (cc)
N-(3,4-Dihydro-2H-1,4-benzoxazin-6-yl)-4-oxo-4,5,6,7-tetrahydro-1H-indole-
-3-carboxamide (Compound 33); mp 216.degree. C. (dd)
N-(2,2-Dimethyl-1,3-benzodioxol-5-yl)-4-oxo-4,5,6,7-tetrahydro-1H-indole--
3-carboxamide (Compound 34). (ee)
N-(2,3-Dihydro-1H-indol-5-yl)-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carbox-
amide (Compound 35); mp 283-286.degree. C. (ff)
N-(2,3-Dihydro-1H-indol-6-yl)-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carbox-
amide (Compound 13); mp 322-323.degree. C. (gg)
N-(1,3-Benzodioxol-5-yl)-4-oxo-5,5-dimethyl-4,5,6,7-tetrahydro-1H-indole--
3-carboxamide (Compound 36). (hh)
N-(2,3-Dihydro-1,4-benzodioxin-6-yl)-4-oxo-5,5-dimethyl-4,5,6,7-tetrahydr-
o-1H-indole-3-carboxamide (Compound 37); mp 241-243.degree. C. (ii)
N-(4H-1,3-Benzodioxin-7-yl)-4-oxo-5,5-dimethyl-4,5,6,7-tetrahydro-1H-indo-
le-3-carboxamide (Compound 38); mp 251-252.degree. C. (jj)
N-(1,3-Benzodioxol-5-yl)-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-
-3-carboxamide (Compound 39); mp 210-212.degree. C. (kk)
N-(2,3-Dihydro-1,4-benzodioxin-6-yl)-4-oxo-1,4,5,6,7,8-hexahydro-cyclohep-
ta[b]pyrrole-3-carboxamide (Compound 12); mp 222-223.degree. C.
(ll)
N-(2,2-Dimethyl-1,3-benzodioxol-5-yl)-4-oxo-6-methyl-4,5,6,7-tetrahydro-1-
H-indole-3-carboxamide (Compound 40); mp 155-157.degree. C. (mm)
N-(1,3-Benzodioxol-5-yl)-4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-ca-
rboxamide (Compound 41); mp 297-299.degree. C. (nn)
N-(2,3-Dihydro-1,4-benzodioxin-6-yl)-4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-
-indole-3-carboxamide (Compound 42); mp 290-292.degree. C. (oo)
N-(1,3-Benzodioxol-5-yl)-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole--
3-carboxamide (Compound 43); mp 245-246.degree. C. (pp)
N-(2,3-Dihydro-1,4-benzodioxin-6-yl)-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydr-
o-1H-indole-3-carboxamide (Compound 44). (qq)
N-(4H-1,3-Benzodioxin-7-yl)-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indo-
le-3-carboxamide (Compound 45); mp 234-236.degree. C. (rr)
N-[(2-Hydroxyethoxy)pyrid-5-yl]-4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indo-
le-3-carboxamide (Compound 15); mp 221-223.degree. C. (ss)
N-(3,4-Dihydro-2H-1,4-benzoxazin-7-yl)-4-oxo-4,5,6,7-tetrahydro-1H-indole-
-3-carboxamide (Compound 46). (tt)
N-[4-(2-Pyrrolidinylethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-c-
arboxamide; [alternate name:
(4-oxo(5,6,7-trihydroindol-3-yl))-N-[4-(2-pyrrolidinylethoxy)phenyl]carbo-
xamide] (Compound 47); (uu)
N-[3-(2-Dimethylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3--
carboxamide [alternate name:
(4-oxo(5,6,7-trihydroindol-3-yl))-N-[4-(2-Dimethylaminoethoxy)phenyl]carb-
oxamide] (Compound 48); (vv)
N-[3-(2-n-Propylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3--
carboxamide (Compound 49). (ww)
N-[3-(2-n-Butylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-c-
arboxamide (Compound 50). (xx)
N-[3-(2-Isobutylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3--
carboxamide (Compound 51) (syrup). (yy)
N-[3-(2-Cyclobutylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole--
3-carboxamide (Compound 52). (zz)
N-[3-(2-t-Butylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-c-
arboxamide (Compound 53). (aaa)
N-[3-(2-Cyclopropylmethylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H--
indole-3-carboxamide (Compound 54). (bbb)
N-{3-[2-(4-Methylcyclohexyl)aminoethoxy]phenyl}-4-oxo-4,5,6,7-tetrahydro--
1H-indole-3-carboxamide (Compound 55). (ccc)
N-{3-[2-(3-Trifluoromethylbenzylamino)ethoxy]phenyl}-4-oxo-4,5,6,7-tetrah-
ydro-1H-indole-3-carboxamide (Compound 56). (ddd)
N-{3-[3-(3-Trifluoromethylbenzylamino)propoxy]phenyl}-4-oxo-4,5,6,7-tetra-
hydro-1H-indole-3-carboxamide (Compound 57). (eee)
N-[4-(2-Dimethylaminoethyl)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-c-
arboxamide (Compound 58). (fff)
N-[4-(2-Pyrrolidin-1-ylethyl)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-
-carboxamide (Compound 59); mp 184-186.degree. C. (ggg)
N-[4-(2-Diisopropylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-
-3-carboxamide (Compound 60). (hhh)
N-[4-(2-Methylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-ca-
rboxamide (Compound 61). (iii)
N-[4-(2-Ethylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-car-
boxamide (Compound 62); mp 140-141.degree. C. (jjj)
N-[2-Fluoro-4-(2-ethylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-ind-
ole-3-carboxamide (Compound 63). (kkk)
N-[4-(2-n-Propylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3--
carboxamide (Compound 64); mp 130-133.degree. C. (lll)
N-[2-Fluoro-4-(2-n-propylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H--
indole-3-carboxamide (Compound 65). (mmm)
N-[3-Fluoro-4-(2-n-propylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H--
indole-3-carboxamide (Compound 66). (mmm-a)
N-[3-Fluoro-4-(2-n-propylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H--
indole-3-carboxamide hydrochloride (Compound 67); mp 373.degree. C.
(nnn)
N-[4-(2-Cyclopropylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-
-3-carboxamide (Compound 68). (ooo)
N-[4-(2-Isopropylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-
-carboxamide (Compound 69); mp 284-286.degree. C. (ppp)
N-[4-(2-Cyclopropylmethylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H--
indole-3-carboxamide (Compound 70). (ppp-a)
N-[4-(2-Cyclopropylmethylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H--
indole-3-carboxamide hemifumarate (Compound 71); mp 234-234.degree.
C. (qqq)
N-[2-Fluoro-4-(2-Cyclopropylmethylaminoethoxy)phenyl]-4-oxo-4,5,6,7-
-tetrahydro-1H-indole-3-carboxamide (Compound 72); mp
247-250.degree. C. (rrr)
N-[3-Fluoro-4-(2-Cyclopropylmethylaminoethoxy)phenyl]-4-oxo-4,5,6,7-
-tetrahydro-1H-indole-3-carboxamide (Compound 73). (rrr-a)
N-[3-Fluoro-4-(2-Cyclopropylmethylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetra-
hydro-1H-indole-3-carboxamide tosylate (Compound 74); mp
222.degree. C. (sss)
N-[4-(2-Isobutylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-ind-
ole-3-carboxamide (Compound 75); dust. (ttt)
N-[2-Fluoro-4-(2-Isobutylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H--
indole-3-carboxamide (Compound 76); mp 152-155.degree. C. (uuu)
N-[3-Fluoro-4-(2-Isobutylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H--
indole-3-carboxamide (Compound 77); mp 147-149.degree. C. (vvv)
N-[4-(2-n-Butylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-c-
arboxamide (Compound 78). (vvv-a)
N-[4-(2-n-butylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-c-
arboxamide hydrochloride (Compound 79); mp 187-190.degree. C. (www)
N-[3-Fluoro-4-(2-n-butylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-i-
ndole-3-carboxamide (Compound 80). (xxx)
N-[4-(2-t-Butylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-c-
arboxamide (Compound 81); mp 290-292.degree. C. (yyy)
N-[3-Fluoro-4-(2-t-butylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-i-
ndole-3-carboxamide (Compound 82). (aaaa)
N-[4-(2-adamant-2-ylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-
e-3-carboxamide (Compound 83); mp 144-149.degree. C. (bbbb)
N-{4-[(R)-Pyrrolidin-2-ylmethoxy]phenyl}-4-oxo-4,5,6,7-tetrahydro-1H-indo-
le-3-carboxamide (Compound 84); mp 164-167-170.degree. C. (cccc)
N-{4-[(S)-Pyrrolidin-2-ylmethoxy]phenyl}-4-oxo-4,5,6,7-tetrahydro-1H-indo-
le-3-carboxamide (Compound 85); mp 165-167.degree. C. (dddd)
N-[4-(Piperidin-3-ylmethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3--
carboxamide (Compound 86). (dddd-a)
N-[4-(Piperidin-3-ylmethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3--
carboxamide hydrochloride (Compound 87); mp 196-199.degree. C.
(eeee)
N-[4-(2-Dimethylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3--
carboxamide (Compound 88); mp 201.degree. C. (ffff)
N-[3-Fluoro-4-(2-dimethylaminoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H--
indole-3-carboxamide (Compound 89); mp 203.degree. C. (gggg)
N-[4-(2-Pyrrolidin-1-ylethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole--
3-carboxamide (Compound 90); mp 164-168.degree. C. (hhhh)
N-[4-(2-Imidaz-1-ylethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-ca-
rboxamide (Compound 91); mp 226-230.degree. C. (iiii)
N-[3-Fluoro-4-(2-moropholin-1-ylethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1-
H-indole-3-carboxamide (Compound 92); mp 200.degree. C. (jjjj)
N-[3-Fluoro-4-(2-pyrrolidin-1-ylethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1-
H-indole-3-carboxamide (Compound 93). (kkkk)
N-[4-(2-Piperidin-2-ylethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-
-carboxamide (Compound 94); mp 281-285.degree. C. (llll)
N-{4-[3-(2,2,2,-Trifluoroethyl)aminopropoxy]phenyl}-4-oxo-4,5,6,7-tetrahy-
dro-1H-indole-3-carboxamide (Compound 95). (mmmm)
N-[4-(3-Isopropylaminopropoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole--
3-carboxamide (Compound 96). (nnnn)
N-{4-[3-(2-Methylpropyl)aminopropoxy]phenyl}-4-oxo-4,5,6,7-tetrahydro-1H--
indole-3-carboxamide (Compound 97). (oooo)
N-[4-(3-Isobutylaminopropoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-
-carboxamide (Compound 98). (pppp)
N-[4-(3-Cyclopropylmethylaminopropoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-
-indole-3-carboxamide (Compound 99). (qqqq)
N-{4-[3-(3-Ethylpropyl)aminopropoxy]phenyl}-4-oxo-4,5,6,7-tetrahydro-1H-i-
ndole-3-carboxamide (Compound 100). (rrrr)
N-[4-(3-Cyclopentylaminopropoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-
e-3-carboxamide (Compound 101). (ssss)
N-{4-[3-(N-Cyclopropylmethyl,N-propyl)aminopropoxy]phenyl}-4-oxo-4,5,6,7--
tetrahydro-1H-indole-3-carboxamide (Compound 102). (tttt)
N-[4-(2-Methylaminoethoxy)pyrid-3-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indole--
3-carboxamide (Compound 103). (uuuu)
N-[4-(2-Ethylaminoethoxy)pyrid-3-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-
-carboxamide (Compound 104). (uuuu-a)
N-[4-(2-Ethylaminoethoxy)pyrid-3-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-
-carboxamide hydrochloride (Compound 105); mp 178-180.degree. C.
(vvvv)
N-[4-(2-n-Propylaminoethoxy)pyrid-3-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-
e-3-carboxamide (Compound 106). (vvvv-a)
N-[4-(2-n-Propylaminoethoxy)pyrid-3-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-
e-3-carboxamide hydrochloride (Compound 107); mp 177-178.degree. C.
(wwww)
N-[4-(2-Isopropylaminoethoxy)pyrid-3-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indo-
le-3-carboxamide (Compound 108). (wwww-a)
N-[4-(2-Isopropylaminoethoxy)pyrid-3-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indo-
le-3-carboxamide hydrochloride (Compound 109); mp 167-169.degree.
C. (xxxx)
N-[4-(2-n-Butylaminoethoxy)pyrid-3-yl]-4-oxo-4,5,6,7-tetrahydro-1H-
-indole-3-carboxamide (Compound 110). (xxxx-a)
N-[4-(2-n-Butylaminoethoxy)pyrid-3-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-
-3-carboxamide hydrochloride (Compound 111); mp 157-159.degree. C.
(yyyy)
N-[4-(2-t-Butylaminoethoxy)pyrid-3-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-
-3-carboxamide (Compound 112); mp 274-278.degree. C. (zzzz)
N-[4-(2-Benzylaminoethoxy)pyrid-3-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indole--
3-carboxamide (Compound 113) (zzzz-a)
N-[4-(2-Benzylaminoethoxy)pyrid-3-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indole--
3-carboxamide hydrochloride (Compound 114); mp 143-145.degree. C.
(aaaaa-a)
N-[4-(Pyrid-3-ylmethoxy)pyrid-3-yl]-4-oxo-4,5,6,7-tetrahydro-1H-
-indole-3-carboxamide (Compound 115). (aaaaa)
N-[4-(Pyrid-3-ylmethoxy)pyrid-3-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3--
carboxamide hydrochloride (Compound 116); mp 276-277.degree. C.
(bbbbb)
N-[4-(Pyrid-4-ylmethoxy)pyrid-3-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3--
carboxamide (Compound 117). (bbbbb-a)
N-[4-(Pyrid-4-ylmethoxy)pyrid-3-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3--
carboxamide hydrochloride (Compound 118); mp 293.degree. C. (ccccc)
N-{4-[(R)-Pyrrolidn-2-ylmethoxy]pyrid-3-yl}-4-oxo-4,5,6,7-tetrahydro-1H-i-
ndole-3-carboxamide (Compound 119); mp 195-198.degree. C. (ccccc-a)
N-{4-[(R)-Pyrrolidn-2-ylmethoxy]pyrid-3-yl}-4-oxo-4,5,6,7-tetrahydro-1H-i-
ndole-3-carboxamide hydrochloride (Compound 120); mp
289-291.degree. C. (ddddd)
N-{4-[(S)-Pyrrolidn-2-ylmethoxy]pyrid-3-yl}-4-oxo-4,5,6,7-tetrahy-
dro-1H-indole-3-carboxamide (Compound 121); mp 138-141.degree. C.
(eeeee)
N-[4-(2-Dimethylaminoethoxy)pyrid-3-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indol-
e-3-carboxamide (Compound 122); mp 163-166.degree. C. (fffff)
N-[4-(3-Dimethylaminopropoxy)pyrid-3-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indo-
le-3-carboxamide (Compound 123); mp 247.degree. C. (ggggg)
N-[4-(2-Pyrrolidin-1-ylethoxy)pyrid-3-yl]-4-oxo-4,5,6,7-tetrahydro-1H-ind-
ole-3-carboxamide (Compound 124) (ggggg-a)
N-[4-(2-Pyrrolidin-1-ylethoxy)pyrid-3-yl]-4-oxo-4,5,6,7-tetrahydro-1H-ind-
ole-3-carboxamide hydrochloride (Compound 125); mp 188-245.degree.
C. (d). (hhhhh)
N-[4-(2-Dimethylaminoethoxy)pyrid-3-yl]-4-oxo-4,5,6,7-tetrahydro--
1H-indole-3-carboxamide (Compound 126). (iiiii)
N-{4-[2-(4-Methyl-piperazin-1-yl)ethoxy]pyrid-3-yl}-4-oxo-4,5,6,7-tetrahy-
dro-1H-indole-3-carboxamide (Compound 127). (jjjjj)
N-{4-[2-Morpholin-1-ylethoxy]pyrid-3-yl}-4-oxo-4,5,6,7-tetrahydro-1H-indo-
le-3-carboxamide (Compound 128). (kkkkk)
N-{4-[2-Piperidin-1-ylethoxy]pyrid-3-yl}-4-oxo-4,5,6,7-tetrahydro-1H-indo-
le-3-carboxamide (Compound 129). (kkkkk-a)
N-{4-[2-Piperidin-1-ylethoxy]pyrid-3-yl}-4-oxo-4,5,6,7-tetrahydro-1H-indo-
le-3-carboxamide hydrochloride (Compound 130); mp 208-211.degree.
C. (lllll)
N-{4-[(1-Methyl-pyrrolidin-3-yl)methoxy]pyrid-3-yl}-4-oxo-4,5,6,7-
-tetrahydro-1H-indole-3-carboxamide (Compound 131); mp
209-211.degree. C. (mmmmm)
N-{4-[(1-Ethyl-pyrrolidin-3-yl)methoxy]pyrid-3-yl}-4-oxo-4,5,6,7--
tetrahydro-1H-indole-3-carboxamide (Compound 132). (nnnnn)
N-{4-[2-(1-Methyl-pyrrolidin-2-yl)ethoxy]pyrid-3-yl}-4-oxo-4,5,6,7-tetrah-
ydro-1H-indole-3-carboxamide (Compound 133). (ooooo)
N-{4-[2-(1-Methyl-pyrrolidin-2-yl)ethoxy]pyrid-3-yl}-4-oxo-4,5,6,7-tetrah-
ydro-1H-indole-3-carboxamide hydrate (Compound 134). (ppppp)
N-[4-(3-n-Propylaminopropoxy)pyrid-3-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indo-
le-3-carboxamide (Compound 135). (qqqqq)
N-[4-(3-Cyclopropylmethylaminopropoxy)pyrid-3-yl]-4-oxo-4,5,6,7-tetrahydr-
o-1H-indole-3-carboxamide (Compound 136). (rrrrr)
N-{4-[3-(2-Ethylbutyl)aminopropoxy]pyrid-3-yl}-4-oxo-4,5,6,7-tetrahydro-1-
H-indole-3-carboxamide (Compound 137). (sssss)
N-[4-(3-Cyclohexylaminopropoxy)pyrid-3-yl]-4-oxo-4,5,6,7-tetrahydro-1H-in-
dole-3-carboxamide (Compound 138). (ttttt)
N-[4-(3-Cyclohexylmethylaminopropoxy)pyrid-3-yl]-4-oxo-4,5,6,7-tetrahydro-
-1H-indole-3-carboxamide (Compound 139). (uuuuu)
N-{4-[3-(Pyrid-4-ylmethyl)aminopropoxy]pyrid-3-yl}-4-oxo-4,5,6,7-tetrahyd-
ro-1H-indole-3-carboxamide (Compound 140). (vvvvv)
N-[4-(2-Pyrrolidin-1-ylethoxy)pyrid-3-yl]-4-oxo-4,5,6,7-tetrahydro-1H-ind-
ole-3-carboxamide (Compound 141); mp 148-150.degree. C. (wwwww)
N-[4-(3-Di-n-propylaminopropoxy)pyrid-3-yl]-4-oxo-4,5,6,7-tetrahydro-1H-i-
ndole-3-carboxamide (Compound 142). (xxxxx)
N-{4-[3-Di(c-propylmethyl)aminopropoxy]pyrid-3-yl}-4-oxo-4,5,6,7-tetrahyd-
ro-1H-indole-3-carboxamide (Compound 143). (yyyyy)
N-{4-[3-Di(2-ethylbutyl)aminopropoxy]pyrid-3-yl}-4-oxo-4,5,6,7-tetrahydro-
-1H-indole-3-carboxamide (Compound 144). (zzzzz)
N-{4-[3-Di(pyrid-4-ylmethyl)aminopropoxy]pyrid-3-yl}-4-oxo-4,5,6,7-tetrah-
ydro-1H-indole-3-carboxamide (Compound 145). (aaaaaa)
N-{4-[2-(2-Pyrrolidin-1-ylethoxy)ethoxy]pyrid-3-yl}-4-oxo-4,5,6,7-tetrahy-
dro-1H-indole-3-carboxamide (Compound 146). (bbbbbb)
N-{4-[2-(2,2-Dimethylaminoethylamino)-2-oxoethyl]phenyl}-4-oxo-4,5,6,7-te-
trahydro-1H-indole-3-carboxamide (Compound 147). (cccccc)
N-{4-[2-(4-Methylaminopiperizin-1yl)-2-oxoethyl]phenyl}-4-oxo-4,5,6,7-tet-
rahydro-1H-indole-3-carboxamide (Compound 148); oil. (dddddd)
N-{4-[7-azabicyclo(2.2.1)hept-2-yloxy]phenyl}-4-oxo-1,4,5,6,7,8-hexahydro-
-cyclohepta[b]pyrrole-3-carboxamide (Compound 149). (eeeeee)
N-[3-(2-Diethylaminoethoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta-
[b]pyrrole-3-carboxamide (Compound 150). (ffffff)
N-[3-(2-Pyrrolidin-1-ylethoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohe-
pta[b]pyrrole-3-carboxamide (Compound 151). (gggggg)
N-[3-(2-Di-Isopropylaminoethoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclo-
hepta[b]pyrrole-3-carboxamide (Compound 152). (hhhhhh)
N-[3-(2-n-Propylaminoethoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohept-
a[b]pyrrole-3-carboxamide (Compound 153). (iiiiii)
N-[3-(2-n-Butylaminoethoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta-
[b]pyrrole-3-carboxamide (Compound 154). (jjjjjj)
N-[3-(Methylaminopropoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b-
]pyrrole-3-carboxamide (Compound 155). (kkkkkk)
N-{3-[3-(N-Ethyl,N-Methyl)aminopropoxy]phenyl}-4-oxo-1,4,5,6,7,8-hexahydr-
o-cyclohepta[b]pyrrole-3-carboxamide (Compound 156). (llllll)
N-{3-[3-(N-Cyclopropylmethyl,N-n-propyl)aminopropoxy]phenyl}-4-oxo-1,4,5,-
6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 157).
(mmmmmm)
N-[3-(Azeditinylpropoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cycl-
ohepta[b]pyrrole-3-carboxamide (Compound 158). (nnnnnn)
N-[3-(3-Ethylaminopropoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[-
b]pyrrole-3-carboxamide (Compound 159). (oooooo)
N-{3-{3-(2,2,2-Trifluoroethyl)aminopropoxy]phenyl}-4-oxo-1,4,5,6,7,8-hexa-
hydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 160). (pppppp)
N-[3-(3-n-Propylaminopropoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohep-
ta[b]pyrrole-3-carboxamide (Compound 161). (rrrrrr)
N-[3-(3-Isopropylaminopropoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohe-
pta[b]pyrrole-3-carboxamide (Compound 163). (ssssss)
N-[3-(3-Cyclopropylaminopropoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclo-
hepta[b]pyrrole-3-carboxamide (Compound 164). (tttttt)
N-[3-(3-Cyclopropylmethylaminopropoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-
-cyclohepta[b]pyrrole-3-carboxamide (Compound 165). (uuuuuu)
N-[3-(3-Cyclobutylaminopropoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cycloh-
epta[b]pyrrole-3-carboxamide (Compound 166). (vvvvvv)
N-[3-(3-Cyclohexylaminopropoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cycloh-
epta[b]pyrrole-3-carboxamide (Compound 167). (wwwwww)
N-{3-[3-(3-Ethylpropyl)aminopropoxy]phenyl}-4-oxo-1,4,5,6,7,8-hexahydro-c-
yclohepta[b]pyrrole-3-carboxamide (Compound 168). (xxxxxx)
N-{3-[3-(2-Methylpropyl)aminopropoxy]phenyl}-4-oxo-1,4,5,6,7,8-hexahydro--
cyclohepta[b]pyrrole-3-carboxamide (Compound 169). (yyyyyy)
N-[3-(3-Isobutylaminopropoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohep-
ta[b]pyrrole-3-carboxamide (Compound 170). (zzzzzz)
N-[3-(3-t-Butylaminopropoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohept-
a[b]pyrrole-3-carboxamide (Compound 171). (aaaaaaa)
N-{3-[3-(2-Methylbutyl)aminopropoxy]phenyl}-4-oxo-1,4,5,6,7,8-hexahydro-c-
yclohepta[b]pyrrole-3-carboxamide (Compound 172). (bbbbbbb)
N-[3-(3-Isoamylaminopropoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohept-
a[b]pyrrole-3-carboxamide (Compound 173). (ccccccc)
N-{3-[3-(4-Methylpentyl)aminopropoxy]phenyl}-4-oxo-1,4,5,6,7,8-hexahydro--
cyclohepta[b]pyrrole-3-carboxamide (Compound 174). (ddddddd)
N-{3-[3-(1,1-Dimethylpropyl)aminopropoxy]phenyl}-4-oxo-1,4,5,6,7,8-hexahy-
dro-cyclohepta[b]pyrrole-3-carboxamide (Compound 175). (eeeeeee)
N-{3-[3-(3,3,-Dimethylbutyl)aminopropoxy]phenyl}-4-oxo-1,4,5,6,7,8-hexahy-
dro-cyclohepta[b]pyrrole-3-carboxamide (Compound 176). (fffffff)
N-{3-[3-(2,4-Dimethylpent-3-yl)aminopropoxy]phenyl}-4-oxo-1,4,5,6,7,8-hex-
ahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 177). (ggggggg)
N-{3-[3-(4-Methylcyclohexyl)aminopropoxy]phenyl}-4-oxo-1,4,5,6,7,8-hexahy-
dro-cyclohepta[b]pyrrole-3-carboxamide (Compound 178). (hhhhhhh)
N-{3-[3-(4-t-Butylcyclohexyl)aminopropoxy]phenyl}-4-oxo-1,4,5,6,7,8-hexah-
ydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 179). (iiiiiii)
N-{3-[3-(2,6-Dimethylcyclohexyl)aminopropoxy]phenyl}-4-oxo-1,4,5,6,7,8-he-
xahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 180).
(jjjjjjj)
N-{3-[3-(1-Phenylethyl)aminopropoxy]phenyl}-4-oxo-1,4,5,6,7,8-hexahydro-c-
yclohepta[b]pyrrole-3-carboxamide (Compound 181). (kkkkkkk)
N-[3-(3-Norborn-2-ylaminopropoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cycl-
ohepta[b]pyrrole-3-carboxamide (Compound 182). (lllllll)
N-[3-(3-Adamant-1-ylaminopropoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cycl-
ohepta[b]pyrrole-3-carboxamide (Compound 183); mp 175-176.degree.
C. (mmmmmmm)
N-[3-(3-Norborn-2-ylmethylaminopropoxy)phenyl]-4-oxo-1,4,5,6,7,-
8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 184).
(nnnnnnn)
N-[3-(3-Adamant-2-ylaminopropoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cycl-
ohepta[b]pyrrole-3-carboxamide (Compound 185). (ooooooo)
N-[4-(2-Ethylaminoethoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b-
]pyrrole-3-carboxamide (Compound 186). (ooooooo-a)
N-[4-(2-Ethylaminoethoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b-
]pyrrole-3-carboxamide hydrochloride (Compound 187); mp
227-228.degree. C. (ppppppp)
N-[2-Fluoro-4-(2-Ethylaminoethoxy)phenyl]-4-oxo-1,4,5,6,7,8-hex-
ahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 188). (qqqqqqq)
N-[4-(2-n-Propylaminoethoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohept-
a[b]pyrrole-3-carboxamide (Compound 189). (rrrrrrr)
N-[4-(2-Cyclopropylaminoethoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cycloh-
epta[b]pyrrole-3-carboxamide (Compound 190). (sssssss)
N-4-(2-n-Butylaminoethoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[-
b]pyrrole-3-carboxamide (Compound 191). (ttttttt)
N-[4-(3-Ethylaminopropoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[-
b]pyrrole-3-carboxamide (Compound 192). (uuuuuuu)
N-{4-[3-(1-Phenyl-1-methylethyl)aminopropoxy]phenyl}-4-oxo-1,4,5,6,7,8-he-
xahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 193).
(vvvvvvv)
N-[4-(Pyrid-3-ylmethoxy)pyrid-3-yl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohept-
a[b]pyrrole-3-carboxamide (Compound 194); mp 241-243.degree. C.
(wwwwwww)
N-[4-(Pyrid-4-ylmethoxy)pyrid-3-yl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohept-
a[b]pyrrole-3-carboxamide (Compound 195). (wwwwwww-a)
N-[4-(Pyrid-4-ylmethoxy)pyrid-3-yl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohept-
a[b]pyrrole-3-carboxamide hydrochloride (Compound 196); mp
235-240.degree. C. (d). (xxxxxxx)
N-[4-(2-Dimethylaminoethoxy)pyrid-3-yl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclo-
hepta[b]pyrrole-3-carboxamide (Compound 197). (yyyyyyy)
N-[4-(2-Diethylaminoethoxy)pyrid-3-yl]-4-oxo-1,4,5,6,7,8-hexahydro-cycloh-
epta[b]pyrrole-3-carboxamide (Compound 198). (zzzzzzz)
N-[4-(2-Pyrrolidin-1-ylethoxy)pyrid-3-yl]-4-oxo-1,4,5,6,7,8-hexahydro-cyc-
lohepta[b]pyrrole-3-carboxamide (Compound 199). (zzzzzzz-a)
N-[4-(2-Pyrrolidin-1-ylethoxy)pyrid-3-yl]-4-oxo-1,4,5,6,7,8-hexahydro-cyc-
lohepta[b]pyrrole-3-carboxamide hydrochloride (Compound 200); mp
160-162.degree. C. (aaaaaaaa)
N-[4-(2-Piperidin-1-ylethoxy)pyrid-3-yl]-4-oxo-1,4,5,6,7,8-hexahydro-cycl-
ohepta[b]pyrrole-3-carboxamide (Compound 201). (bbbbbbbb)
N-{4-[2-(1-Methyl-pyrrolidin-2-yl)ethoxy]pyrid-3-yl}-4-oxo-1,4,5,6,7,8-he-
xahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 202).
(cccccccc)
N-{4-[(1-Ethyl-pyrrolidin-3-yl)methoxy]pyrid-3-yl}-4-oxo-1,4,5,6,7,8-hexa-
hydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 203); oil.
(dddddddd)
N-[4-(2-Morpholin-1-ylethoxy)pyrid-3-yl]-4-oxo-1,4,5,6,7,8-hexahydro-cycl-
ohepta[b]pyrrole-3-carboxamide (Compound 204). (eeeeeeee)
N-[4-(2-Diethylaminoethoxy)pyrid-3-yl]-4-oxo-1,4,5,6,7,8-hexahydro-cycloh-
epta[b]pyrrole-3-carboxamide (Compound 205). (ffffffff)
N-[4-(2-n-Propylaminoethoxy)pyrid-3-yl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclo-
hepta[b]pyrrole-3-carboxamide (Compound 206). (ffffffff-a)
N-[4-(2-n-Propylaminoethoxy)pyrid-3-yl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclo-
hepta[b]pyrrole-3-carboxamide hydrochloride (Compound 207); mp
210.degree. C. (gggggggg)
N-[4-(2-Isopropylaminoethoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohep-
ta[b]pyrrole-3-carboxamide (Compound 208). (hhhhhhhh)
N-[4-(3-Isopropylaminoproxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohept-
a[b]pyrrole-3-carboxamide (Compound 209). (iiiiiiii)
N-[4-(3-Cyclopropylaminopropoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclo-
hepta[b]pyrrole-3-carboxamide (Compound 210). (jjjjjjjj)
N-[4-(3-Cyclobutylaminopropoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cycloh-
epta[b]pyrrole-3-carboxamide (Compound 211). (kkkkkkkk)
N-[4-(3-Cyclopropylmethylaminopropoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-
-cyclohepta[b]pyrrole-3-carboxamide (Compound 212). (llllllll)
N-[4-(3-Isobutylaminopropoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohep-
ta[b]pyrrole-3-carboxamide (Compound 213). (mmmmmmmm)
N-{4-[3-(2,2-Dimethylpropyl)aminopropoxy]phenyl}-4-oxo-1,4,5,6,7,8-hexahy-
dro-cyclohepta[b]pyrrole-3-carboxamide (Compound 214). (nnnnnnnn)
N-{4-[3-(3-Ethylpropyl)aminopropoxy]phenyl}-4-oxo-1,4,5,6,7,8-hexahydro-c-
yclohepta[b]pyrrole-3-carboxamide (Compound 215). (oooooooo)
N-{4-[3-(2-Methylbutyl)aminopropoxy]phenyl}-4-oxo-1,4,5,6,7,8-hexahydro-c-
yclohepta[b]pyrrole-3-carboxamide (Compound 216). (pppppppp)
N-{4-[3-(2-Methylpropyl)aminopropoxy]phenyl}-4-oxo-1,4,5,6,7,8-hexahydro--
cyclohepta[b]pyrrole-3-carboxamide (Compound 217). (qqqqqqqq)
N-[4-(3-i-Pentylaminopropoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cyclohep-
ta[b]pyrrole-3-carboxamide (Compound 218). (rrrrrrrr)
N-[4-(3-Cyclohexylaminopropoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cycloh-
epta[b]pyrrole-3-carboxamide (Compound 219). (ssssssss)
N-{4-[3-(N-Cyclopropylmethyl,N-n-propyl)aminopropoxy]phenyl}-4-oxo-1,4,5,-
6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide (Compound 220).
(tttttttt)
N-[4-(3-Indan-2-ylaminopropoxy)phenyl]-4-oxo-1,4,5,6,7,8-hexahydro-cycloh-
epta[b]pyrrole-3-carboxamide (Compound 221). (uuuuuuuu)
N-[3-Fluoro-4-(2-ethoxy-2-oxoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-i-
ndole-3-carboxamide (Compound 222); mp 192-196.degree. C.
(vvvvvvvv)
N-[3-Fluoro-4-(2-hydroxy-2-oxoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-1H--
indole-3-carboxamide (Compound 223); mp 246-248.degree. C.
(wwwwwwww)
N-[3-Fluoro-4-(2-ethylamino-2-oxoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro--
1H-indole-3-carboxamide (Compound 224). (xxxxxxxx)
N-[3-Fluoro-4-(2-diethylamino-2-oxoethoxy)phenyl]-4-oxo-4,5,6,7-tetrahydr-
o-1H-indole-3-carboxamide (Compound 225); mp 193-196.degree. C.
(yyyyyyyy)
N-{3-Fluoro-4-[2-(4-methylpiperizin-1-yl)-2-oxoethoxy]phenyl}-4-oxo-4,5,6-
,7-tetrahydro-1H-indole-3-carboxamide (Compound 226). (zzzzzzzz)
N-ethyl-N-[2-(ethylamino)ethyl]-2-{4-[(4-oxo-(4,5,6,7-tetrahydroindol-3-y-
l))carbonylamino]phenoxy}acetamide (Compound 227). (aaaaaaaaa)
N-[2-(dipropylamino)ethyl]-2-{4-[(4-oxo-(4,5,6,7-tetrahydroindol-3-yl))ca-
rbonylamino]phenoxy}acetamide (Compound 228); mp 148-150.degree. C.
(bbbbbbbbb)
N-[2-(diethylamino)ethyl]-N-methyl-2-{4-[(4-oxo-(4,5,6,7-tetrahydroindol--
3-yl))carbonylamino]phenoxy}acetamide (Compound 229); mp
220-228.degree. C. (ccccccccc)
N-[2-(diethylamino)ethyl]-N-ethyl-2-{4-[(4-oxo-(4,5,6,7-tetrahydroindol-3-
-yl))carbonylamino]phenoxy}acetamide (Compound 230); mp
165-167.degree. C. (ddddddddd)
N-[4-(2-morpholin-4-yl-2-oxoethoxy)phenyl](4-oxo-(4,5,6,7-tetrahydroindol-
-3-yl))carboxamide (Compound 231). (eeeeeeeee)
N-[3-fluoro-4-(2-morpholin-4-yl-2-oxoethoxy)phenyl](4-oxo-(4,5,6,7-tetrah-
ydroindol-3-yl))carboxamide (Compound 232); mp 110.degree. C.
(fffffffff)
(4-oxo-(4,5,6,7-trihydroindol-3-yl))-N-[4-(2-oxo-2-piperazinylethoxy)phen-
yl]carboxamide (Compound 233) (ggggggggg)
N-[3-(diethylamino)propyl]-2-{4-[(4-oxo-(4,5,6,7-tetrahydroindol-3-yl))ca-
rbonylamino]phenoxy}acetamide (Compound 234) (hhhhhhhhh)
N-[3-(diethylamino)propyl]-2-{2-fluoro-4-[(4-oxo-(4,5,6,7-tetrahydroindol-
-3-yl))carbonylamino]phenoxy}acetamide (Compound 235). (iiiiiiiii)
N-[4-(diethylamino)-1-methylbutyl]-2-{4-[(4-oxo-(4,5,6,7-tetrahydroindol--
3-yl))carbonylamino]phenoxy}acetamide (Compound 236). (jjjjjjjjj)
N-[4-(diethylamino)-1-methylbutyl]-2-{2-fluoro-4-[(4-oxo-(4,5,6,7-tetrahy-
droindol-3-yl))carbonylamino]phenoxy}acetamide (Compound 237).
Example 4
The compounds shown in Tables I and II were prepared using methods
similar to those given in Schemes I-IV and further illustrated by
Examples 1 and 2.
TABLE-US-00002 TABLE I ##STR00099## Cmd # Name G Spectral Data 238
N-{4-(2-(ethyl-methanesulfonyl-amino)-ethoxy]phenyl}-4-oxo-
4,5,6,7-tetrahydro-1H-indole-3-carboxamide ##STR00100## LRMS calcd
419 found [M + 1] 239
N-[4-(3-methanesulfonyl-propoxy)phenyl]-4-oxo-4,5,6,7-tetrahydro-
1H-indole-3-carboxamide ##STR00101## LRMS calcd 390 found [M + 1]
391 240 N-4-{4-(2-(ethanesulfonyl-ethyl-amino)ethoxy]-phenyl}-oxo-
4,5,6,7-tetrahydro-1H-indole-3-carboxamide ##STR00102## LRMS calcd
433 found [M + 1] 434 241
N-(4-{2-[ethyl-(propane-1-sulfonyl)amino]ethoxy}phenyl)-4-oxo-
4,5,6,7-tetrahydro-1H-indole-3-carboxamide ##STR00103## LRMS calcd
447 found [M + 1] 448 242
N-(4-{2-[ethyl-(thiophene-3-sulfonyl)amino]ethoxy}phenyl)-4-oxo-
4,5,6,7-tetrahydro-1H-indole-3-carboxamide ##STR00104## LRMS calcd
504 found [M + 1] 505 243
N-{6-[2-(ethyl-methanesulfonyl-amino)ethoxy]pyridin-3-yl}-4-oxo-
4,5,6,7-tetrahydro-1H-indole-3-carboxamide ##STR00105## LRMS calcd
420 found [M + 1] 421 244
N-[6-(1-benzyl-1H-imidazol-2-ylmethoxy)-pyridin-3-yl]-4-oxo-
4,5,6,7-tetrahydro-IH-indole-3-carboxamide ##STR00106## LRMS calcd
441 found [M + 1] 442 245
N-[2-(2-aminoethoxy)pyridin-3-yl]-4-oxo-4,5,6,7-tetrahydro-1H-
indole-3-carboxamide ##STR00107## LRMS calcd 314 found [M + 1] 315
246 N-[6-(2-ethanesulfonylamino-ethoxy)pyridin-3-yl]-4-oxo-4,5,6,7-
tetrahydro-1H-indole-3-carboxamide ##STR00108## LRMS calcd 406
found [M + 1] 407 247
N-[6-(2-methanesulfonylamino-ethoxy)-pyridin-3-yl]-4-oxo-4,5,6,7-
tetrahydro-1H-indole-3-carboxamide ##STR00109## LRMS calcd 392
found [M + 1]393 248
N-[4-(2-methanesulfonylamino-ethoxy)phenyl]-4-oxo-4,5,6,7-
tetrahydro-1H-indole-3-carboxamide ##STR00110## LRMS calcd 391
found [M + 1] 392 249
N-4-Oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid[2-(2-
methanesulfonylamino-ethoxy)-pyridin-3-yl]-amide ##STR00111## LRMS
calcd 392 found [M + 1] 393 250
N-{2-[2-(thiophene-2-sulfonylamino)ethoxy]pyridin-3-yl}-4-oxo-
4,5,6,7-tetrahydro-1H-indole-3-carboxamide ##STR00112## LRMS calcd
460 found [M + 1] 461 251
N-{6-[(pyridin-2-ylmethyl)-amino]-pyridin-3-yl}-4-oxo-4,5,6,7-
tetrahydro-1H-indole-3-carboxamide ##STR00113## LRMS calcd 361
found [M + 1] 362 252
N-{6-[(pyridin-3-ylmethyl)-amino]-pyridin-3-yl}-4-oxo-4,5,6,7-
tetrahydro-1H-indole-3-carboxamide ##STR00114## LRMS calcd 361
found [M + 1] 362 253
N-(4-ethoxy-3-fluoro-phenyl)-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-
carboxamide ##STR00115## LRMS calcd 316 found [M + 1] 317 254
N-acid[3-(2-ethoxy-ethoxy)-phenyl]-4-Oxo-4,5,6,7-tetrahydro-1H-
indole-3-carboxamide ##STR00116## LRMS calcd 342 found [M + 1] 343
255
N-(4-[1,2,4]triazol-1-ylmethyl-phenyl)-4-oxo-4,5,6,7-tetrahydro-1H-
indole-3-carboxamide ##STR00117## LRMS calcd 335 found [M + 1] 336
256 N-{4-[2-(methanesulfonyl-methyl-amino)-ethyl]-phenyl}-4-oxo-
4,5,6,7-tetrahydro-1H-indole-3-carboxamide ##STR00118## LRMS calcd
389 found [M + 1] 390 257
N-[4-(2-methanesulfonylamino-ethyl)-phenyl]-4-oxo-4,5,6,7-
tetrahydro-1H-indole-3-carboxamide ##STR00119## LRMS calcd 375
found [M + 1] 378 258
N-(4-methanesulfonylmethyl-phenyl)-4-oxo-4,5,6,7-tetrahydro-1H-
indole-3-carboxamide ##STR00120## LRMS calcd 346 found [M + 1] 347
259 N-[4-(4-hydroxymethyl-imidazol-1-yl)-phenyl]-4-oxo-4,5,6,7-
tetrahydro-1H-indole-3-carboxamide ##STR00121## LRMS calcd 350
found [M + 1] 351 260
N-[4-(2-methanesulfonyl-ethyl)-phenyl]-4-oxo-4,5,6,7-tetrahydro-
1H-indole-3-carboxamide ##STR00122## LRMS calcd 360 found [M + 1]
361 261
(2-{4-[(4-Oxo-4,5,6,7-tetrahydro-1H-indole-3-carbonyl)-amino]-
phenyl}-ethyl)-carbamic acid tert-butyl ester ##STR00123## LRMS
calcd 397 found [M + 1] 398 262
N-[4-(2-imidazol-1-yl-ethyl)-phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-
indole-3-carboxylic acid amide ##STR00124## LRMS calcd 348 found [M
+ 1] 349 263
N-{4-[2-(thiophene-2-sulfonylamino)-ethyl]-phenyl}-4-oxo-4,5,6,7-
tetrahydro-1H-indole-3-carboxamide ##STR00125## LRMS calcd 443
found [M + 1] 444 264
N-[4-(2-ethanesulfonylamino-ethyl)-phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-
- indole-3-carboxamide ##STR00126## LRMS calcd 389 found [M + 1]
390 265
N-{4-(2-(propane-1-sulfonylamino)ethyl]phenyl}-4-oxo-4,5,6,7-
tetrahydro-1H-indole-3-carboxamide ##STR00127## LRMS calcd 403
found [M + 1] 404 266
N-(5-ethoxy-pyridin-2-yl)-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-
carboxamide ##STR00128## LRMS calcd 378 found [M + 1] 379 267
N-[4-(3-methanesulfonylamino-propoxy)-phenyl]-4-oxo-4,5,6,7-
tetrahydro-1H-indole-3-carboxamide ##STR00129## LRMS calcd 405
found [M + 1] 406 268
N-[4-(3-amino-propoxy)-phenyl]-4-oxo-4,5,6,7-tetrahydro-1H-
indole-3-carboxamide ##STR00130## LRMS calcd 327 found [M + 1] 328
269
N-(5-propoxy-pyridin-2-yl)-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-
carboxamide ##STR00131## LRMS calcd 299 found [M + 1] 300 270
N-(5-propoxy-pyridin-2-yl)-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-
carboxamide ##STR00132## LRMS calcd 313 found [M + 1] 314 271
N-imidazo[1,2-a]pyridin-6-yl-4-Oxo-4,5,6,7-tetrahydro-1H-indole-3-
carboxamide ##STR00133## LRMS calcd 294 found [M + 1] 295 272
N-(6-(3-(4-pyridinyl)propoxy)-3-pyridinyl)-4,5,6,7-tetrahydro-4-oxo-
1H-indole-3-carboxamide ##STR00134## electrospray mass spectrum:
m/z 391 [M + 1] 273
N-(6-(3-(3-pyridinyl)propoxy)-3-pyridinyl)-4,5,6,7-tetrahydro-4-oxo-
1H-indole-3-carboxamide ##STR00135## electrospray mass spectrum:
m/z 391 [M + 1] 274
N-(6-(3-(2-pyridinyl)propoxy)-3-pyridinyl)-4,5,6,7-tetrahydro-4-oxo-
1H-indole-3-carboxamide ##STR00136## electrospray mass spectrum:
m/z 391 [M + 1] 275
N-(6-(2-(2-pyridinyl)ethoxy)-3-pyridinyl)-4,5,6,7-tetrahydro-4-oxo-
1H-indole-3-carboxamide ##STR00137## electrospray mass spectrum:
m/z 375 [M - 1] 276
N-[2-(ethylamino)pyrid-5-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-
carboxamide ##STR00138## M.W. 298.348; MS (M + 1) 299 277
N-[2-(methylarnino)pyrid-5-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-
3-carboxamide ##STR00139## M.W. 284.321; MS (M + 1) 285. 278
N-{2-[2-(pyrrolidin-1-yl)ethylamino]pyrid-5-yl}-4-oxo-4,5,6,7-
tetrahydro-1H-indole-3-carboxamide ##STR00140## M.W. 298.348; MS (M
+ 1) 299. 279
N-[2-(propylamino)pyrid-5-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-
3-carboxamide ##STR00141## M.W. 312.375; MS (M + 1) 313 280
N-{2-[(2-methoxyethyl)amino]pyrid-5-yl}-4-oxo-4,5,6,7-
tetrahydro-1H-indole-3-carboxamide ##STR00142## M.W. 328.375; MS (M
+ 1) 329 281
N-[2-(butylamino)pyrid-5-yl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-
3-carboxamide ##STR00143## M.W. 326.402; MS (M + 1) 327. 282
N-(6-ethoxypyridazin-3-yl)-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-
carboxamide ##STR00144## M.W. 300.321; MS (M + 1) 301 283
N-(6-methoxypyridazin-3-yl)-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-
carboxamide ##STR00145## M.W. 286.294; MS (M + 1) 287. 284
N-[6-(propylamino)pyridazin-3-yl]-4-oxo-4,5,6,7-tetrahydro-1H-
indole-3-carboxamide ##STR00146## M.W. 313.363; MS (M + 1) 314. 285
N-[2-ethoxy-6-(ethylamino)pyrid-3-yl]-4-oxo-4,5,6,7-tetrahydro-1H-
indole-3-carboxamide ##STR00147## M.W. 300.321; MS (M + 1) 301. 286
N-{2-[N-methyl(ethylamino)]pyrid-5-yl}-1-methyl-4-oxo-
4,5,6,7-tetrahydro-1H-indole-3-carboxamide ##STR00148## M.W.
286.294; MS (M + 1) 287. 287
N-{2-[(2-methylpropyl)amino]pyrid-5-yl}-4-oxo-4,5,6,7-
tetrahydro-1H-indole-3-carboxamide ##STR00149## M.W. 326.402; MS (M
+ 1) 327 288
N-[2-(acetamido)pyrid-5-yl]-4-oxo-4,5,6,7-tetrahydro-1H-
indole-3-carboxamide ##STR00150## M.W. 312.332; MS (M + 1) 313. 289
N-[2-(N-ethylacetamido)pyrid-5-yl]-4-oxo-4,5,6,7-tetrahydro-1H-
indole-3-carboxamide ##STR00151## M.W. 340.386; MS (M + 1) 341 290
N-{2-[2-(morpholin-4-yl)ethylamino]pyrid-5-yl}-4-oxo-4,5,6,7-
tetrahydro-1H-indole-3-carboxamide ##STR00152## M.W. 383.450; MS (M
+ 1) 384 291
N-(2-{[2-(N-methylacetamido)ethyl]amino}pyrid-5-yl)-4-oxo-
4,5,6,7-tetrahydro-1H-indole-3-carboxamide ##STR00153## M.W.
369.428; MS (M + 1) 370. 292
N-(2-ethoxy-4-methylpyrid-5-yl)-4-oxo-4,5,6,7-tetrahydro-1H-
indole-3-carboxamide ##STR00154## M.W. 313.360; MS (M + 1) 314. 304
4-Oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid{4-[2-
(thiophene-2-sulfonylamino)-ethoxy]phenyl}-amide ##STR00155## 305
4-Oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid(4-[1,2,4]-
triazol-1-yl-phenyl)-amide ##STR00156## LRMS calcd 321; found [M +
1] 322 306 4-Oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic
acid{4-[3-
(1-methyl-1H-imidazole-4-sulfonylamino)-propoxy]-phenyl}amide
##STR00157## LRMS calcd 471; found [M + 1] 472 307
4-Oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid imidazo
[1,2-a]pyridin-5-ylamide ##STR00158## LRMS calcd 294; found [M + 1]
295 308 4-Oxo-3a,4,5,6,7,7a-hexahydro-1H-indole-3-carboxylic
acid[6-(3- propyl-[1,2,4]thidazol-5-ylamino)-pyridin-2-yl]amide
##STR00159## .sup.1H NMR (CD.sub.3OD) 0.75-0.95(m, 3H), 1.62-
1.81(m, 5H), 2.60-2.75(m, 5H), 6.07(d, 1H)8.6(s, 1H) LCMS found [M
+ H] 305.2
TABLE-US-00003 TABLE II ##STR00160## Cmd. # Name G Spectral Data
293
N-[6-(2-pyridin-3-yl-ethylamino)-pyridin-2-yl]-4-oxo-3a,4,5,6,7,7a-
hexahydro-1H-indole-3-carboxylic acidamide ##STR00161## LCMS found
(M + H) 299.3 294
N-[6-(3-imidazol-1-yl-propylamino)-pyridin-2-yl)-4-oxo-3a,4,5,6,7,7a-
hexahydro-1H-indole-3-carboxamide ##STR00162## LCMS found (M + H)
379.3 295
N-[6-(3-propyl[1,2,4]thiadiazol-5-ylamino)-pyridin-2-yl]-4-oxo-
3a,4,5,6,7,7a-hexahydro-1H-indole-3-carboxamide ##STR00163## LCMS
found (M + H) 305.2 296
N-(6-ethylaminopyridin-2-yl)-4-oxo-3a,4,5,6,7,7a-hexahydro-1H-indole-3-
- carboxylic acid ##STR00164## LCMS found (M + H) 299.3 297
4-oxo-3a,4,5,6,7,7a-hexahydro-1H-indole-3-carboxylic
acid{6-(2-ethyl- imidazol-1yl)ethoxy)-pyridin-3-yl}amide
##STR00165## LCMS found (M + H) 394.4 298
4-oxo-3a,4,5,6,7,7a-hexahydro-1H-indole-3-carboxylic
acid[6-(2-imidazol- 1-yl-ethoxy)-pyridin-3-yl)-amide ##STR00166##
LCMS found (M + H) 366.4
Example 5
Intermediate Compounds
The intermediate compounds shown in TABLE III are prepared using
the methods given in Schemes III and IV.
TABLE-US-00004 TABLE III Cmp # Scheme Name Structure Data 299 3
N-Ethyl-pyridine-2,6-diamine ##STR00167## LCMS found (M + H) 125
300 3 N-(3-Imidazol-1-yl-propyl)-pyridine-2,6-diamine ##STR00168##
LCMS found (M + H) 218 301 3
N-(2-Pyridin-2-yl-ethyl)-pyridine-2,6-diamine ##STR00169## LCMS
found (M + H) 215 302 4 4-(2-Imidazol-1-yl-ethoxy)-phenylamine
##STR00170## LCMS found (M + H) 204 303 4
4-[2-(2-Ethyl-imidazol-1-yl)-ethoxy]phenylamine ##STR00171## LCMS
found (M + H) 232
Example 5
Water solubility for various compounds within the invention was
determined and compared with that for compounds outside the scope
of the invention. The compounds evaluated are encompassed by
Formula II:
TABLE-US-00005 TABLE IV ##STR00172## Formula II Water Solubility
(ug/ml) Rx Ry n R 23 H H 1 ##STR00173## 203 H H 1 ##STR00174## 143
H H 2 ##STR00175## 15 H H 1 ##STR00176## 1.0 H H 1 ##STR00177##
0.58 H H 1 ##STR00178## 0.34 H H 1 ##STR00179## 0.26 CH.sub.3
CH.sub.3 1 ##STR00180##
Example 6
Preparation of Radiolabeled Probe Compounds of the Invention
The compounds of the invention are prepared as radiolabeled probes
by carrying out their synthesis using precursors comprising at
least one atom that is a radioisotope. The radioisotope is
preferably selected from of at least one of carbon (preferably
.sup.14C), hydrogen (preferably .sup.3H), sulfur (preferably
.sup.35S), or iodine (preferably .sup.125I). Such radiolabeled
probes are conveniently synthesized by a radioisotope supplier
specializing in custom synthesis of radiolabeled probe compounds.
Such suppliers include Amersham Corporation, Arlington Heights,
Ill.; Cambridge Isotope Laboratories, Inc. Andover, Mass.; SRI
International, Menlo Park, Calif.; Wizard Laboratories, West
Sacramento, Calif.; ChemSyn Laboratories, Lexena, Kans.; American
Radiolabeled Chemicals, Inc., St. Louis, Mo.; and Moravek
Biochemicals Inc., Brea, Calif.
Tritium labeled probe compounds are also conveniently prepared
catalytically via platinum-catalyzed exchange in tritiated acetic
acid, acid-catalyzed exchange in tritiated trifluoroacetic acid, or
heterogeneous-catalyzed exchange with tritium gas. Tritium labeled
probe compounds can also be prepared, when appropriate, by sodium
borotritide reduction. Such preparations are also conveniently
carried out as a custom radiolabeling by any of the suppliers
listed in the preceding paragraph using the compound of the
invention as substrate.
Example 7
Receptor Autoradiography
Receptor autoradiography (receptor mapping) is carried out in vitro
as described by Kuhar in sections 8.1.1 to 8.1.9 of Current
Protocols in Pharmacology (1998) John Wiley & Sons, New York,
using radiolabeled compounds of the invention prepared as described
in the preceding Example.
Example 8
Binding Assay
This assay is a standard assay for GABA.sub.A binding affinity. The
high affinity and high selectivity of compounds of this invention
for the benzodiazepine site of the GABA.sub.A receptor is confirmed
using the binding assay described in Thomas and Tallman (J. Bio.
Chem. 1981; 156:9838-9842, and J. Neurosci. 1983; 3:433-440).
Rat cortical tissue is dissected and homogenized in 25 volumes
(w/v) of Buffer A (0.05 M Tris HCl buffer, pH 7.4 at 4.degree. C.).
The tissue homogenate is centrifuged in the cold (4.degree. C.) at
20,000.times.g for 20 minutes. The supernatant is decanted, the
pellet rehomogenized in the same volume of buffer, and centrifuged
again at 20,000.times.g. The supernatant of this centrifugation
step is decanted and the pellet stored at -20.degree. C. overnight.
The pellet is then thawed and resuspended in 25 volumes of Buffer A
(original wt/vol), centrifuged at 20,000.times.g and the
supernatant decanted. This wash step is repeated once. The pellet
is finally resuspended in 50 volumes of Buffer A.
Incubations containing 100 .mu.l of tissue homogenate, 100 .mu.l of
radioligand, (0.5 nM .sup.3H-Ro15-1788 [.sup.3H-Flumazenil],
specific activity 80 Ci/mmol), and test compound or control (see
below), and are brought to a total volume of 500 .mu.l with Buffer
A. Incubations are carried for 30 min at 4.degree. C. and then
rapidly filtered through Whatman GFB filters to separate free and
bound ligand. Filters are washed twice with fresh Buffer A and
counted in a liquid scintillation counter. Nonspecific binding
(control) is determined by displacement of .sup.3H Ro15-1788 with
10 .mu.M Diazepam (Research Biochemicals International, Natick,
Mass.). Data were collected in triplicate, averaged, and percent
inhibition of total specific binding (Total Specific
Binding=Total-Nonspecific) was calculated for each compound.
A competition binding curve is obtained with up to 11 points
spanning the compound concentration range from 10.sup.-12M to
10.sup.-5M obtained per curve by the method described above for
determining percent inhibition. K.sub.i values are calculated
according the Cheng-Prussof equation. When tested in this assay
preferred compounds of the invention exihibit K.sub.i values of
less than 1 uM, more preferred compounds of the invention have
K.sub.i values of less than 500 nM, still more preferred compounds
of the invention have K.sub.i values of less than 100 nM, and even
more preferred compounds have K.sub.i values of less than 10
nM.
Results for several compounds of this invention are listed in Table
V.
TABLE-US-00006 TABLE V Compound Number K.sub.i (nM) 1 90 2 29 3 49
4 0.24 5 9 6 9 7 30 8 27 9 1.3 10 37 11 7 12 5 13 24 14 3 15 12
Example 9
Electrophysiology
The following assay is used to determine if a compound of the
invention act as an agonist, an antagonist, or an inverse agonist
at the benzodiazepine site of the GABA.sub.A receptor.
Assays are carried out as described in White and Gurley
(NeuroReport 6: 1313-1316, 1995) and White, Gurley, Hartnett,
Stirling, and Gregory (Receptors and Channels 3: 1-5, 1995) with
modifications. Electrophysiological recordings are carried out
using the two electrode voltage-clamp technique at a membrane
holding potential of -70 mV. Xenopus laevis oocytes are
enzymatically isolated and injected with non-polyadenylated cRNA
mixed in a ratio of 4:1:4 for .alpha., .beta. and .gamma. subunits,
respectively. Of the nine combinations of .alpha., .beta. and
.gamma. subunits described in the White et al. publications,
preferred combinations are .alpha..sub.1.beta..sub.2.gamma..sub.2,
.alpha..sub.2.beta..sub.3.gamma..sub.2,
.alpha..sub.3.beta..sub.3.gamma..sub.2, and
.alpha..sub.5.beta..sub.3.gamma..sub.2. Preferably all of the
subunit cRNAs in each combination are human clones or all are rat
clones. The sequence of each of these cloned subunits is available
from GENBANK, e.g., human .alpha..sub.1, GENBANK accession no.
X14766, human .alpha..sub.2, GENBANK accession no. A28100; human
.alpha..sub.3, GENBANK accession no. A28102; human .alpha..sub.5,
GENBANK accession no. A28104; human .alpha..sub.2, GENBANK
accession no. M82919; human .beta..sub.3, GENBANK accession no.
Z20136; human .beta..sub.2, GENBANK accession no. X15376; rat
.alpha..sub.1, GENBANK accession no. L08490, rat .alpha..sub.2,
GENBANK accession no. L08491; rat .alpha..sub.3, GENBANK accession
no. L.sub.08492; rat .alpha..sub.5, GENBANK accession no. L08494;
rat .beta..sub.2, GENBANK accession no. X15467; rat .beta..sub.3,
GENBANK accession no. X15468; and rat .gamma..sub.2, GENBANK
accession no. L08497. For each subunit combination, sufficient
message for each constituent subunit is injected to provide current
amplitudes of >10 nA when 1 .mu.M GABA is applied.
Compounds are evaluated against a GABA concentration that evokes
<10% of the maximal evokable GABA current (e.g. 1 .mu.M-9
.mu.M). Each oocyte is exposed to increasing concentrations of
compound in order to evaluate a concentration/effect relationship.
Compound efficacy is calculated as a percent-change in current
amplitude: 100*((Ic/I)-1), where Ic is the GABA evoked current
amplitude observed in the presence of test compound and I is the
GABA evoked current amplitude observed in the absence of the test
compound.
Specificity of a compound for the benzodiazepine site is determined
following completion of a concentration/effect curve. After washing
the oocyte sufficiently to remove previously applied compound, the
oocyte is exposed to GABA+1 .mu.M RO15-1788, followed by exposure
to GABA+1 .mu.M RO15-1788+ test compound. Percent change due to
addition of compound is calculated as described above. Any percent
change observed in the presence of RO15-1788 is subtracted from the
percent changes in current amplitude observed in the absence of 1
.mu.M RO15-1788. These net values are used for the calculation of
average efficacy and EC.sub.50 values by standard methods. To
evaluate average efficacy and EC.sub.50 values, the
concentration/effect data are averaged across cells and fit to the
logistic equation.
The invention and the manner and process of making and using it,
are now described in such full, clear, concise and exact terms as
to enable any person skilled in the art to which it pertains, to
make and use the same. It is to be understood that the foregoing
describes preferred embodiments of the present invention and that
modifications may be made therein without departing from the spirit
or scope of the present invention as set forth in the claims. To
particularly point out and distinctly claim the subject matter
regarded as invention, the following claims conclude this
specification.
* * * * *